Inositol trisphosphate receptors in smooth muscle cells
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Inositol trisphosphate receptors in smooth muscle cells
Am J Physiol Heart Circ Physiol 302: H2190 –H2210, 2012. First published March 23, 2012; doi:10.1152/ajpheart.01146.2011. Review Inositol trisphosphate receptors in smooth muscle cells Damodaran Narayanan, Adebowale Adebiyi, and Jonathan H. Jaggar Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee Submitted 8 December 2011; accepted in final form 22 March 2012 inositol 1,4,5-trisphosphate receptors; sarcoplasmic reticulum; calcium (Ca2⫹) signals are produced by both extracellular Ca2⫹ influx and intracellular Ca2⫹ release (22, 29). Ca2⫹ influx can occur through plasma membrane ion channels and transporters, including voltage-dependent L-type Ca2⫹ (CaV1.2) channels, nonselective cation channels, and the Na⫹/Ca2⫹ exchanger (22, 29). Ca2⫹ can also be released from intracellular stores, such as the sarcoplasmic reticulum (SR)/ endoplasmic reticulum (ER) and mitochondria (22, 29). Ca2⫹ signals in smooth muscle cells (SMCs) include Ca2⫹ flashes, oscillations, puffs, ripples, sparklets, sparks, waves, and global intracellular Ca2⫹ concentration ([Ca2⫹]i) (13, 26, 90, 144, 158, 254). These diverse Ca2⫹ signals regulate physiological functions and are modified in diseases, leading to pathological consequences. Many plasma membrane receptors couple via heteromeric Gq/11 proteins to PLC (22, 29). Upon agonist to receptor binding, PLC-catalyzed hydrolysis of phosphatidylinositol 4,5bisphosphate generates diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (21, 57). IP3 binds to and activates INTRACELLULAR CALCIUM Address for reprint requests and other correspondence: J. H. Jaggar, Dept. of Physiology, Univ. of Tennessee Health Science Center, Memphis, TN 38163 (e-mail: jjaggar@uthsc.edu). H2190 SR-localized IP3 receptors (IP3Rs) (21, 57). SMC IP3Rs were first purified from aorta and, following reconstitution into phospholipid vesicles, were identified as Ca2⫹ release channels (34, 52, 134). IP3Rs regulate many cellular processes in SMCs, including contractility, gene expression, migration, and proliferation (2, 60, 149, 156, 234, 237). The focus of this review is to discuss IP3R expression, cellular localization, channel activity, communication with ion channels and organelles, Ca2⫹ signals generated, physiological functions regulated, and pathological alterations in SMCs. Excellent reviews have summarized knowledge gained from studies of recombinant IP3R channels and those expressed in a wide variety of different cell types (21, 57, 143, 171). Here, IP3R signaling in non-SMC types will only be considered when extrapolation to SMCs is appropriate or when discussion may stimulate future research in SMCs. IP3R Structure IP3Rs are tetramers, with each subunit composed of three principal regions: an NH2 terminus, a hydrophobic region comprising six transmembrane domains, and a COOH-terminal tail (Fig. 1) (139, 246). The cytosolic NH2-terminal region is functionally divided into the IP3-binding domain, a suppressor 0363-6135/12 Copyright © 2012 the American Physiological Society http://www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Narayanan D, Adebiyi A, Jaggar JH. Inositol trisphosphate receptors in smooth muscle cells. Am J Physiol Heart Circ Physiol 302: H2190 –H2210, 2012. First published March 23, 2012; doi:10.1152/ajpheart.01146.2011.—Inositol 1,4,5trisphosphate receptors (IP3Rs) are a family of tetrameric intracellular calcium (Ca2⫹) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP3R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca2⫹ signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP3R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP3R channel activity. SMC IP3Rs communicate with nearby ryanodine-sensitive Ca2⫹ channels and mitochondria to influence SR Ca2⫹ release and reactive oxygen species generation. IP3R-mediated Ca2⫹ release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca2⫹ channels. SMC IP3Rs also signal to other proteins via SR Ca2⫹ release-independent mechanisms through physical coupling to TRP channels and local communication with large-conductance Ca2⫹activated potassium channels. IP3R-mediated Ca2⫹ release generates a wide variety of intracellular Ca2⫹ signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP3R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP3R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP3R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP3R signaling contributing to disease. Review IP3Rs IN SMOOTH MUSCLE CELLS H2191 domain that inhibits IP3 binding, and the regulatory domain (Fig. 1, A and B) (57, 245). The regulatory domain contains binding sites for ATP (Fig. 1A, red squares) and Ca2⫹ (Fig. 1A, blue squares) and consensus sequences for phosphorylation (Fig. 1A, black squares) (57, 139, 171). A coupling domain through which IP3Rs physically interact with transient receptor potential canonical (TRPC) channels is also located in the regulatory domain (Fig. 1B) (2, 208). The transmembrane domains anchor each IP3R subunit to the SR membrane (Fig. 1, B and C) (139). The luminal loop between transmembrane domains 5 and 6 forms the Ca2⫹-permeable pore (Fig. 1B) (139). The COOH-terminal tail extends from transmembrane domain 6 into the cytosol (Fig. 1, A and B) (139). The transmembrane domains and COOH-terminal tail appear to be essential for IP3R tetramerization (141, 188). IP3R Isoforms and Distribution in SMCs of Different Tissues To date, three IP3R isoforms (IP3R1–3) have been identified, each of which is encoded by a different gene (57). Important features of mammalian IP3R isoforms are summarized in Table 1. SMCs express all three IP3R isoforms, with relative levels of each determined by the tissue of origin and developmen- tal stage. IP3R1 is the predominant isoform expressed in vascular SMCs (64, 84, 147, 228, 254, 257). Quantitative PCR performed on isolated cerebral artery SMCs indicated that IP3R1 mRNA was the most abundant of the three isoforms, at 82% of total message, with much of the residual IP3R message being IP3R3 (254). Similarly, IP3R1 was the major isoform detected in basilar and mesenteric arteries, whole thoracic aorta, cultured portal vein SMCs, and A7r5 cells, an aortic SMC line (64, 84, 147, 211, 228, 257). Reports indicate that IP3R isoform expression in vascular SMCs shifts during ontogeny and proliferation (210, 211). In neonatal (2- to 4-day-old) rats, IP3R1 protein was lower and IP3R3 protein was higher in SMCs of aorta and portal vein, compared with those in juvenile (6 wk-old) rats (210). IP3R2 and IP3R3 levels were higher in proliferating, cultured aortic SMCs than in whole aorta homogenates (211). IP3R isoform expression in nonvascular SMCs exhibits tissue variability. In isolated ureteric and myometrial SMCs, all three IP3R isoforms were detected (26, 148). IP3R3 was the predominant isoform, with IP3R1 and IP3R2 also present in tracheal SMCs (230). In contrast, cultured ureteric and gastric SMCs expressed IP3R1 and IP3R3 but not IP3R2 (147, 154). Tissue variability in IP3R isoform expression may contribute to signaling differences in these SMC types. AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Fig. 1. Inositol 1,4,5-trisphosphate receptor (IP3R) molecular structure. A: schematic representation of an IP3R subunit depicting important domains and regions. Sites for ATP-binding (black squares), Ca2⫹-binding (blue squares), and phosphorylation (red squares) are indicated. B: single IP3R subunit illustrating important domains, regions, and pore. C: tetrameric IP3R channel. SR, sarcoplasmic reticulum; N, NH2 terminus; C, COOH terminus. Review H2192 IP3Rs IN SMOOTH MUSCLE CELLS Table 1. Important features of the three mammalian IP3R isoforms IP3R1 IP3R2 – Homology with human IP3R1 IP3R3 77% (242) 72% (123, 242) Alternative splicing Yes (163, 241) None described None described Amino acid number (human) 2,695–2,743 (splice variation-dependent) (69, 163, 241) 3p25–26 (241) 2,701 (242) 2,671 (123, 242) 12p11 (242) 6p21 (242) Chromosomal localization (human) Cellular localization in SMCs Central SR Peripheral SR Cultured aorta (199, 211) Cultured aorta (199, 211) Cultured aorta (199, 211) Cultured aorta (199, 211), ureter (26) Highest (0.10 M)* (217) Lowest [0.40 M]* (217) Yes [0.17 M]* (216) Yes [0.37 M]* (216) Decreases (33, 244) Yes [0.15 M]* (216) Yes [0.16 M]* (216) None described Yes [0.06 M]* (216) Yes [0.17 M]* (216) ⬍500 nM increases, ⬎500 nM decreases (33, 244) 3–4 (171) High [0.13 mM]* (217) 1 (171) None (217) 2 (171) Low [2.0 mM]* (217) IP3Rs, inositol 1,4,5-trisphosphate receptors; SMCs, smooth muscle cells; SR, sarcoplasmic reticulum. Numbers in parenthesis indicate reference numbers. *EC50 for recombinant IP3Rs reconstituted into lipid bilayer. Cellular Expression and Localization of SMC IP3Rs Cellular levels of IP3Rs in SMCs are determined by an equilibrium between gene transcription and protein degradation (3, 129, 171, 227). c-Myb, a transcription factor, binds to the IP3R1 promoter and stimulates transcription in cultured aortic SMCs (3). In A7r5 cells, retinoic acid inhibited IP3R1 gene transcription through a mechanism mediated by activator protein-2, another transcription factor (45). In cultured aortic SMCs, hydrogen peroxide (H2O2) stimulated proteasomal degradation of IP3R1 and IP3R3, whereas Jak2, a tyrosine kinase, phosphorylated IP3R1 and prevented proteasomal degradation (129, 227). Transforming growth factor- (TGF-) reduced IP3R1 and IP3R3 protein in renal arteriolar SMCs, although it was not determined if this was due to protein degradation (138). In A7r5 cells, vasopressin inhibited IP3R1 gene transcription and also stimulated protein degradation, suggesting that a physiological agonist can modulate SMC IP3R levels through both of these mechanisms (197). Therefore, regulation of both gene transcription and protein degradation controls IP3R cellular levels in SMCs. In SMCs, IP3Rs locate to the SR in different cellular regions, including central SR around the nucleus and peripheral SR beneath the plasma membrane (Table 1) (2, 26, 63, 162, 199, 211, 224, 254). IP3R localization to central and/or peripheral SR is isoform and tissue dependent. In cerebral artery SMCs, IP3R1 distributes to both central and peripheral SR (Fig. 2A) (2, 254). However, IP3R1 and IP3R3 located only to peripheral SR in ileal and ureteric SMCs, respectively (26, 63). IP3Rs on central SR around the nucleus may regulate Ca2⫹-dependent gene expression through signals that do not impact global [Ca2⫹]i. Distribution to peripheral SR may position IP3Rs in close proximity to the plasma membrane, thereby permitting local signaling to membrane proteins, including ion channels (2, 255). Therefore, IP3R cellular localization in SMCs likely contributes to distinct physiological functions regulated by these proteins. IP3R Channel Properties in Vascular SMCs Single channel properties of vascular SMC IP3Rs have been examined using purified aortic IP3Rs reconstituted into planar lipid bilayers (134). Reconstituted IP3Rs were found to be IP3-gated ion channels, most permeable to Ca2⫹, followed by K⫹ and Cl⫺ (134). Bath application of 0.5 M IP3 activated ⬃32-pS single channel currents after a delay of ⬃1 min in standard buffer with 50 mM Ca2⫹ as the charge carrier (Fig. 2B) (134). The delayed response between bath application of IP3 and stimulation of channel currents was suggested to be related to the diffusion of IP3 in the bath (134). IP3-induced channel currents were enhanced by ATP (Fig. 2C) and blocked by heparin (134). The kinetics of IP3R-mediated Ca2⫹ release in vascular SMCs have been investigated using permeabilized portal vein smooth muscle strips and flash photolysis of caged IP3 (198). Binding of IP3 to a single IP3R subunit, as opposed to all four subunits of the tetramer, was sufficient to induce channel opening (198). IP3 photolysis elevated [Ca2⫹]i from ⬃100 to 175 nM, with a total IP3-releasable SR Ca2⫹ pool of ⬃126 M (198). The amount of IP3-induced Ca2⫹ release increased as a function of IP3 concentration ([IP3]) with an estimated Kd of ⬃1 M (198). The delay between IP3 photolysis and the [Ca2⫹]i elevation was inversely proportional to [IP3], with saturating [IP3] (⬎4 M) and submaximal [IP3] (0.4 – 0.8 M) inducing Ca2⫹ release within 10 ms or after 420 ms, respectively (198). Collectively, these studies (134, 198) provided important information regarding biophysical properties of IP3Rs and the kinetics of IP3R-mediated Ca2⫹ release in vascular SMCs. AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 IP3 affinity Regulation by Ca2⫹ Activation Inhibition Effect of Ca2⫹ on IP3 binding Regulation by ATP Number of binding sites Sensitivity Cerebral artery (1, 2, 254), cultured and noncultured aorta (162, 199, 211), A7r5 cells (224) Cerebral artery (1, 2, 254), cultured aorta (199, 211), vas deferens (162), ileum (63) Intermediate [0.27 M]* (217) Review H2193 IP3Rs IN SMOOTH MUSCLE CELLS Cellular Regulators of SMC IP3R Activity This section will describe ligands, protein kinases, regulatory proteins, and other modulators that influence IP3R activity in SMCs. The reader is referred to earlier reviews (57, 127, 172, 213) where additional details of these and other IP3R regulators derived from reports in non-SMC types are discussed. Ligands. Ligands that regulate SMC IP3R activity include IP3, cytosolic Ca2⫹, SR luminal Ca2⫹, and ATP, with IP3 and cytosolic Ca2⫹ acting as principal modulators. Regulation of IP3R channel activity by IP3, cytosolic Ca2⫹ concentration ([Ca2⫹]c), and ATP is summarized in Table 1. IP3 is the major stimulus for inducing IP3R-mediated Ca2⫹ release in SMCs (34, 134, 198). [3H]IP3 binding assays indicated that IP3 bound to IP3Rs with a Kd of 2–5 nM in SMCs of the aorta, colon, ileum, jejeunum, myometrium, and vas deferens (4, 24, 34, 150, 152, 182, 223, 251). Evidence from studies in non-SMCs suggest that binding of IP3 induces a conformational change in the IP3-binding domain, which is transmitted via the central regulatory domain to the transmembrane domains to elicit channel opening (141, 155, 222). SMC IP3R activity is modulated by an intricate interplay between IP3 and [Ca2⫹]c (77, 79, 134). SMC IP3R channel activation occurs at [Ca2⫹]c ⬍300 nM, and released Ca2⫹ initially stimulates IP3Rs via Ca2⫹-induced Ca2⫹ release (CICR) (77, 79). However, an elevation in [Ca2⫹]c ⬎300 nM inhibits SMC IP3Rs (77, 79). Studies (74, 140) in non-SMCs suggested that for Ca2⫹ to inhibit IP3Rs, [Ca2⫹]c ⬎300 nM and CaM, a Ca2⫹-binding protein, were both required. IP3R activity regulation by [Ca2⫹]c is controlled by distinct stimulatory and inhibitory Ca2⫹-binding sites (195, 196). One luminal and seven cytosolic Ca2⫹-binding sites (Fig. 1A, blue squares) have been identified on IP3Rs, suggesting that Ca2⫹ binds to and directly influences IP3R activity (195, 196). A [Ca2⫹]c elevation can also inhibit IP3 binding to SMC IP3Rs, thereby indirectly regulating channel activity (16). Thus [Ca2⫹]c regulates IP3R activity in SMCs via two simultaneously occurring mechanisms: 1) directly, by binding to stimulatory or inhibitory sites on IP3Rs; and 2) indirectly, by modulating IP3 binding to IP3Rs. Evidence also suggests that IP3 determines if Ca2⫹ stimulates or inhibits IP3Rs (124). IP3 binding to IP3Rs displaces Ca2⫹ from inhibitory sites, leading to a reduction in Ca2⫹-dependent inhibition, and exposes stimulatory Ca2⫹binding sites (Fig. 1A, blue squares), thereby permitting Ca2⫹mediated activation (124). Therefore, IP3 and [Ca2⫹]c influence SMC IP3R activity directly, by binding to IP3Rs and indirectly, by modulating effects of each other. SMC IP3Rs are modulated not only by cytosolic Ca2⫹ but also by SR luminal Ca2⫹. In A7r5 cells, an elevation in SR Ca2⫹ concentration ([Ca2⫹]SR) enhanced IP3-induced Ca2⫹ release (30). Depletion of SR Ca2⫹ abolished IP3R-mediated Ca2⫹ release in SMCs (81, 86, 117, 136, 151). Ca2⫹ binding to a site located in the luminal loop between transmembrane domains 5 and 6 of IP3Rs (Fig. 1A, blue square in the pore) (195) stimulated cerebellar IP3Rs (23). [Ca2⫹]SR may also regulate SR Ca2⫹ release in SMCs by determining the driving force for Ca2⫹ efflux, which should modulate the amplitude of IP3R-mediated Ca2⫹ signals. Therefore, [Ca2⫹]SR may influence SMC IP3Rs through more than one mechanism, although experimental evidence for such regulation is limited. ATP binds to three sites located in the IP3R regulatory domain (Fig. 1A, black squares). ATP is not required for SMC IP3R activation but enhances IP3 and Ca2⫹ sensitivity, thereby augmenting channel activity (77, 80, 134). ATP alone did not stimulate aortic IP3Rs reconstituted into planar lipid bilayers but elevated IP3-induced currents (Fig. 2C) (134). Similarly, in permeabilized portal vein SMCs, ATP dose-dependently increased IP3-induced Ca2⫹ release with a maximal effect at 0.5 mM ATP (80). ATP also elevates SMC IP3R Ca2⫹ sensitivity, AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Fig. 2. Smooth muscle cell (SMC) IP3Rs. A: immunofluorescence image illustrating IP3R1 localization in an isolated cerebral artery SMC. Scale bar ⫽ 10 m. B and C: single channel recordings of purified aortic IP3Rs reconstituted into lipid bilayers demonstrating activation by IP3 (⫺50 mV holding potential; B) and ATP-mediated enhancement of IP3-induced currents (C). B and C: reproduced from Mayrleitner et al. (134) by copyright permission (2011) from Elsevier. Review H2194 IP3Rs IN SMOOTH MUSCLE CELLS and FK506 in colonic SMCs (15, 118). In contrast, in aorta, FKBP12 did not coimmunoprecipitate with IP3Rs and IP3Rmediated Ca2⫹ release was unaffected by FK506 or rapamycin (118, 119). Explanations for these tissue-specific differences in FKBP12 regulation of SMC IP3Rs are unclear but may be due to variable expression of FKBP12 and important regulatory proteins, including calcineurin, FK506, and mTOR. RACK1 is a scaffolding protein that shuttles PKC to its substrates, thereby facilitating interaction (173). RACK1 coimmunoprecipitated with IP3R1 in PC12 cells, a non-SMC line, and elevated [3H]IP3 binding to cerebellar IP3Rs, suggesting that RACK1 interacts with IP3Rs and increases IP3 affinity (173). RACK1 enhanced agonist-induced IP3R-mediated Ca2⫹ release in A7r5 cells and cultured preglomerular microvascular SMCs, suggesting that RACK1 also stimulates IP3R channel activity in SMCs (36, 173). Although evidence suggests functional regulation of IP3R-mediated Ca2⫹ release by RACK1 in SMCs, whether these effects are due to direct binding to IP3Rs or by PKC-dependent pathways has not been resolved. Other modulators. In addition to endogenous ligands, kinases, and regulatory proteins, cellular pH and reactive oxygen species (ROS) also modulate SMC IP3Rs. pH influences SMC IP3R activity by controlling IP3 binding and IP3R Ca2⫹ sensitivity (38, 78, 152, 215, 251). Elevating pH activated recombinant IP3R1 and IP3R3 channels, with IP3R1 being more sensitive at pH 6.8 and IP3R3 at pH 7.5, suggesting that pH regulation is isoform dependent (44). IP3 binding to SR membranes from aortic, colonic, and tracheal smooth muscle was weak at pH ⬍7 and maximal at pH 8 –9 (38, 152, 251). In portal vein and taenia caeci SMCs, increasing pH from 6.7 to 7.0 –7.3 reduced the Ca2⫹ concentration required for IP3R activation, thereby elevating IP3R-mediated Ca2⫹ release (78, 215). Evidence suggests that H⫹ may compete with IP3 and Ca2⫹ to inhibit their binding to SMC IP3Rs, resulting in channel inhibition (215). ROS regulate SMC IP3Rs through processes that include control of [IP3]i and modulation of IP3R IP3 affinity (31, 112, 183, 201). Superoxide reduced IP3 hydrolysis in SR vesicles of thoracic aorta, thereby enhancing [IP3]i and IP3-induced Ca2⫹ release (201). Thimerosal, an oxidizing agent, enhanced the affinity of IP3R1 for IP3 and potentiated IP3-induced Ca2⫹ release in A7r5 cells (31). Similarly, in SMCs of the pulmonary and systemic vasculature, H2O2 stimulated IP3R-mediated Ca2⫹ release, suggesting that ROS enhance IP3R signaling in SMCs (112, 183). In contrast, in coronary artery SMCs, H2O2, superoxide, and peroxynitrite inhibited the SR Ca2⫹-ATPase (SERCA), leading to a reduction in [Ca2⫹]SR that attenuated IP3R-mediated Ca2⫹ release (53, 65). In gallbladder and mesenteric artery SMCs, superoxide and H2O2 did not alter IP3R activity (225, 238). Therefore, ROS regulation of SMC IP3Rs is multimodal and may be dependent on tissue of origin and ROS species involved. In summary, IP3, [Ca2⫹]c, and ATP are major modulators of IP3R activity in SMCs and protein kinases, pH, and ROS regulate IP3Rs through phosphorylation, controlling [IP3]i, IP3 binding to IP3Rs, and Ca2⫹ sensitivity of IP3Rs. IP3R Communication with Ion Channels and Mitochondria in SMCs SMC IP3Rs communicate with several SR- and plasma membrane-localized ion channels and mitochondria to control intracellular signals and influence physiological functions. AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 leading to an increase in Ca2⫹ activation, which can augment CICR (77). Thus, in contrast to IP3, which activates IP3Rs by reducing Ca2⫹-mediated inhibition, ATP stimulates IP3Rs by enhancing Ca2⫹-dependent activation (57). In summary, IP3, Ca2⫹, and ATP modulate multiple regulatory processes to control and fine tune IP3R activity in SMCs. Protein kinases. PKA and PKG inhibit SMC IP3Rs via phosphorylation, through regulation of IP3 binding, and by controlling IP3 generation. Consensus sequences for PKA- and PKG-mediated IP3R phosphorylation are located in the regulatory domain of SMC IP3Rs (Fig. 1A, red squares) (43, 100). PKG phosphorylated SMC IP3Rs at serine 1755 and inhibited IP3-induced Ca2⫹ release in aortic and gastric SMCs (100, 154). PKG phosphorylated IP3Rs via IP3R-associated cGMP kinase substrate (IRAG) in gastric and tracheal SMCs (153, 154, 189, 226). PKG/IRAG-dependent IP3R phosphorylation and subsequent inhibition of IP3R-mediated Ca2⫹ release relaxed colonic and aortic SMCs (46, 58). These studies suggest that PKG/IRAG regulation of IP3R phosphorylation and Ca2⫹ release regulates SMC contractility. PKA activation reduced PLC-dependent IP3 generation and decreased the number of binding sites for IP3 on IP3Rs, thereby attenuating IP3Rmediated Ca2⫹ release in tracheal SMCs (120, 191). Twodimensional phosphopeptide mapping revealed that PKA phosphorylated SMC IP3Rs at serine 1589 (43). In iris sphincter SMCs, PKA inhibited IP3R-mediated Ca2⫹ release, resulting in relaxation (48, 204). It has been proposed that PKG is required for PKA-mediated phosphorylation of IP3Rs in SMCs. In gastric SMCs and intact aorta, PKA phosphorylated IP3Rs at two sites: serine 1589, a PKA phosphorylation site, and serine 1755, a PKG-specific site, suggesting that PKA activates PKG to phosphorylate IP3Rs (101, 154). Therefore, PKA-PKG cross talk may contribute to PKA-mediated phosphorylation of SMC IP3Rs. PKC and tyrosine kinases enhance SMC IP3R signaling through IP3R phosphorylation and by elevating intracellular [IP3] ([IP3]i). PKC and tyrosine kinase phosphorylation sites on SMC IP3Rs are yet to be identified. PKC-mediated IP3R phosphorylation elevated [Ca2⫹]i and contracted gallbladder SMCs and A10 cells, an aortic SMC line (240, 248). In cultured aortic SMCs, tyrosine kinase inhibitors reduced ANG II-induced PLC-␥1 phosphorylation and elevations in [IP3]i and [Ca2⫹]i, suggesting that tyrosine kinases stimulate IP3 generation in SMCs (126). Similarly, tyrosine kinase inhibitors attenuated agonistinduced elevations in [IP3]i and [Ca2⫹]i and contraction in cultured gluteal and pulmonary artery SMCs but not in cultured aortic SMCs (55, 214). Collectively, these studies indicate that protein kinases regulate SMC IP3R-mediated Ca2⫹ signaling and contraction directly, through phosphorylation and indirectly, by controlling IP3 generation and IP3 binding. Regulatory proteins. Evidence suggests that cytosolic proteins, including the 12-kDa FK506 binding protein (FKBP12) and receptor for activated PKC 1 (RACK1) influence IP3R channel activity in SMCs (15, 36, 118, 173). FKBP12, an intracellular ligand for immunosuppressants FK506 and rapamycin, interacts with and regulates SMC IP3Rs (15, 118). FKBP12 coimmunoprecipitated with IP3R1 in colonic SMCs, suggesting physical interaction (118). FKBP12 modulated colonic SMC IP3R activity via three effector proteins: calcineurin, FK506, and mammalian target of rapamycin (mTOR) (15, 118). FKBP12 potentiated IP3R-mediated Ca2⫹ release through mTOR and inhibited IP3R activity through calcineurin Review IP3Rs IN SMOOTH MUSCLE CELLS activation (253). Cerebral artery SMC TRPC6 channels also contain a CIRB domain but do not physically couple to IP3R1 due to spatial separation of these proteins (2). IP3R1-induced TRPC3 channel activation induced a cation current (ICat), resulting in membrane depolarization, CaV1.2 channel activation, and vasoconstriction (Fig. 3C) (237). This SR-Ca2⫹ release-independent mechanism is a major contributor to agonist-induced IP3R-mediated global [Ca2⫹]i elevation and vasoconstriction in cerebral arteries (2, 237). SMC IP3Rs also activate TRP channels through SR Ca2⫹ release-dependent mechanisms (61, 106, 206). ET-1-induced IP3R stimulation activated Ca2⫹ influx that was inhibited by TRPC1 knockdown in cultured aortic SMCs (206). IP3Rmediated Ca2⫹ release also activated Ca2⫹-sensitive PKC isoforms, leading to PKC-dependent TRPC1 activation in portal vein SMCs (106). These studies suggested that IP3R stimulation activates TRPC1 channels via SR Ca2⫹ release, although it was unclear if physical coupling was also involved. In cerebral artery SMCs, SERCA and IP3R inhibitors reduced TRPM4-mediated native ICat (61). TRPM4 is Ca2⫹ sensitive and does not contain a CIRB domain (2), indicating that SR-released Ca2⫹ and not direct interaction with IP3Rs is likely to regulate TRPM4 activation. A reduction in SR Ca2⫹ load following IP3R-mediated Ca2⫹ release may feedback to stimulate SOCE, which exists in some but not all contractile and migratory/proliferative SMC types (5, 88, 97, 159, 185, 237, 239). In addition to Orai and STIM proteins, TRP channels may be a molecular component of SOCE channels (73, 180, 229). TRPC channels, including 1, 5, 6, and 7 contribute to SOCE in SMCs of coronary and mesenteric arteries and portal vein (186, 207). IP3R-mediated SR Ca2⫹ depletion activated TRPC-dependent SOCE in SMCs of inferior vena cava, portal vein, and pulmonary arteries (108, 114, 160, 180). SMC TRP channels are also activated by IP3R-independent mechanisms. TRPC channels, including 1, 3, 4, 5, 6, and 7 were activated by pathways that required PLC, phosphatidylinositol 4,5-bisphosphate, and/or DAG, but not IP3 or IP3Rs, in SMCs of coronary, ear, and mesenteric arteries, portal vein, and gastric antrum (5, 6, 93, 109, 110, 174, 185). Therefore, in SMCs, TRP channels are activated by PLC-mediated IP3Rdependent and -independent pathways. IP3R-dependent pathways include physical coupling with TRPC channels, Ca2⫹ release-mediated activation, and SR Ca2⫹ store depletioninduced stimulation. BKCA CHANNELS. SMC IP3Rs communicate with nearby plasma membrane BKCa channels via SR Ca2⫹ release-dependent and -independent mechanisms (255) (Fig. 3D). IP3Rmediated SR Ca2⫹ release activated BKCa channels in basilar artery SMCs (95). IP3R1 is located in close spatial proximity to, and coimmunoprecipitates with, plasma membrane BKCa channels in cerebral artery SMCs (255). SMC IP3R1 activation elevated BKCa channel Ca2⫹ sensitivity, thereby facilitating channel activation at lower Ca2⫹ concentrations in cerebral artery SMCs (255). The IP3R-mediated elevation in BKCa channel Ca2⫹ sensitivity would enhance channel activation by SR Ca2⫹ release by local IP3Rs (255). IP3R-induced BKCa channel activation would oppose TRPC3 channel-mediated membrane depolarization in SMCs and attenuate the IP3induced global [Ca2⫹]i elevation and vasoconstriction (255). MACROMOLECULAR COMPLEXES CONTAINING IP3RS. IP3Rs, TRPC3, and BKCa channels appear to be located in macromolecular AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Ryanodine-sensitive Ca2⫹ release channels. Ryanodine-sensitive Ca2⫹ release channels (RyRs) are tetrameric proteins that share a number of structural and functional characteristics with IP3Rs, including substantial amino acid sequence homology of the pore region and carboxy terminus (59, 142, 247). Analytical cell fractionation studies revealed that RyRs and IP3Rs are both SR membrane localized in SMCs (28, 56, 91). There is uncertainty as to whether IP3Rs and RyRs release Ca2⫹ from the same or distinct pools in SMCs. IP3Rs and RyRs have been suggested to share the same Ca2⫹ pool in SMCs of mesenteric, small pulmonary and renal arteries, portal vein, and small intestine (86, 91, 168, 219, 256). In colonic SMCs, two SR populations were identified: one expressing only RyRs and another with both RyRs and IP3Rs (56). Reports have also suggested that RyRs and IP3Rs do not share the same Ca2⫹ pool and that each channel can generate distinct Ca2⫹ signals in SMCs of the ureter and mesenteric and large pulmonary arteries (26, 32, 91, 219). Some of this discrepancy may have arisen due to different experimental conditions used to obtain data. Whether IP3Rs or RyRs release Ca2⫹ from the same or distinct pools may also depend on anatomical origin and physiological functions of the SMC types studied. Additional data, including that obtained by using identical experimental approaches in different SMC types, will be required to investigate these possibilities. Ca2⫹ released from an IP3R or RyR activates the other channel type via CICR (12, 25, 28, 62, 91, 232). IP3R activation stimulated RyR-mediated Ca2⫹ release in SMCs of gallbladder, gastric antrum, portal vein, and renal artery (12, 25, 28, 62, 91, 232). RyR inhibitors also attenuated norepinephrine- and phenylephrine-induced IP3R-dependent Ca2⫹ release in portal vein and renal artery SMCs (28, 91). Therefore, IP3Rmediated Ca2⫹ release activates RyRs in SMCs and, in turn, RyRs also feedback to regulate IP3R activity. However, ryanodine, a RyR blocker, and anti-RyR channel antibodies did not alter agonist-induced IP3R-mediated Ca2⫹ release in pulmonary artery and ureteric SMCs (39, 91), suggesting that IP3R-RyR cross talk may not exist in all SMC-containing tissues. Plasma membrane-localized ion channels. Research over the last decade has demonstrated that IP3Rs can regulate the activity of plasma membrane TRPC and large-conductance Ca2⫹-activated K⫹ (BKCa) channels through both SR Ca2⫹ release-dependent and -independent mechanisms in SMCs. Evidence suggests that IP3R communication with these ion channels is enabled by caveolae, which are plasma membrane microdomains located between the SR and plasma membranes in many cell types, including SMCs (Fig. 3, A and B). TRPC CHANNELS. IP3R activation stimulates TRPC channels directly, through physical coupling and indirectly, through Ca2⫹-dependent activation and induction of store-operated Ca2⫹ entry (SOCE). Endothelin (ET)-1 and uridine 5=-triphosphate, PLC-coupled receptor agonists, and IP3 stimulated physical coupling between the IP3R1 NH2-terminal TRPC coupling domain and the TRPC3 channel COOH-terminal CaM and IP3R binding (CIRB) domain in cerebral artery SMCs (Fig. 3C) (1, 2, 253). In mammals, the TRPC coupling domain sequence (L⫺⫺⫺⫺⫺⫺EEVWL⫺W⫺D) and the CIRB domain sequence (Y⫺⫺⫺MK⫺LV⫺RYV) are conserved among the three IP3R isoforms and seven TRPC channels, respectively (208). The IP3R coupling domain displaces inhibitory CaM from the TRPC CIRB domain, leading to channel H2195 Review H2196 IP3Rs IN SMOOTH MUSCLE CELLS complexes that span from the SR membrane to plasma membrane caveolae in SMCs. Caveolae disruption, knockdown of caveolin-1 (cav-1), a caveolae scaffolding protein, and a cav-1 scaffolding domain peptide spatially separated IP3R1 and TRPC3 channels and attenuated IP3-induced ICat activation in cerebral artery SMCs (1, 47, 83). Coimmunoprecipitation and immunofluorescence studies indicated that BKCa channels associate with cav-1 in aortic and cerebral artery SMCs (7, 255). Thus cav-1 likely maintains close spatial proximity of SR IP3R1 channels with both TRPC3 and BKCa channels in SMCs (Fig. 3, C and D) (1, 7, 255). Caveolae may permit localized coupling of IP3R1 to both TRPC3 and BKCa channels to modulate SMC membrane potential and arterial contractility. Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Fig. 3. IP3Rs communicate with plasma membrane ion channels in SMCs. A: transmission electron microscopic image of a portal anterior mesenteric vein section illustrating close spatial proximity between junctional SR and plasma membrane. Electron-opaque material (small arrows) traverses the gap of ⬃20 –25 nm between the 2 opposing membranes. B: caveolae, termed “surface vesicles” (SV; small arrows) in the original publication, can be found where the SR and plasma membrane (arrowheads) are in close spatial proximity. A mitochondrion (M) is also located nearby both the SR and plasma membranes (arrowheads). Scale bar ⫽ 100 nm. A and B: reproduced from Devine et al. (47) by copyright permission (2011) of the Rockefeller University Press. C: an elevation in intracellular IP3 concentration ([IP3]i) elevation induces physical coupling of IP3R1 to transient receptor potential canonical 3 (TRPC3) channels in arterial SMCs, leading to vasoconstriction. D: IP3R1 activation elevates the Ca2⫹ sensitivity of nearby large-conductance Ca2⫹-activated K⫹ (BKCa) channels, thereby amplifying stimulation by released Ca2⫹ to oppose IP3-induced SMC contraction. DAG, diacylglycerol. Therefore, IP3Rs, TRPC3, and BKCa channels appear to be located within the same cav-1-containing macromolecular complex that bridges the SR and plasma membrane in arterial SMCs (1, 255). RyRs generate Ca2⫹ sparks that activate nearby plasma membrane BKCa channels in SMCs, inducing relaxation (90, 159). Given that SMC RyR channels can be located immediately (⬃20 nm) beneath the plasma membrane (90), IP3Rs and RyRs may also be contained within the same macromolecular complexes and communicate locally to each other and nearby plasma membrane ion channels. Conceivably, SMC RyRs may communicate with TRP and BKCa channels, thereby regulating membrane potential and contractility. Future research should be directed at exploring cellular localiza- AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Review H2197 IP3Rs IN SMOOTH MUSCLE CELLS Ca2⫹ (175, 187). In SMCs, physiological global [Ca2⫹]i, which is ⬃100 –300 nM, should not modify [Ca2⫹]mito (175, 187), a conclusion supported by published data (156). Local high [Ca2⫹]i elevations generated by nearby Ca2⫹ channels are necessary to elevate SMC [Ca2⫹]mito (35, 175). Receptor agonists that elevate IP3 and activate IP3Rs increase [Ca2⫹]mito to micromolar concentrations in permeabilized A10 cells and in cultured preglomerular afferent arteriole, cultured and noncultured aortic, pulmonary artery, and colonic SMCs (50, 66, 137, 146, 169, 176). SMC [Ca2⫹]mito measurements in these studies were obtained primarily by using inorganic fluorescent indicators. Recent evidence (156) obtained using a genetically encoded mitochondria-targeting Ca2⫹ indicator (2mt8CG2) indicated that IP3R-mediated Ca2⫹ waves, but not global [Ca2⫹]i, elevated [Ca2⫹]mito and stimulated mitochondria-derived ROS generation in cerebral artery SMCs (Fig. 4B). This study provided evidence that in arterial SMCs, Ca2⫹ waves may be the IP3R-mediated Ca2⫹ signal that communicates with Fig. 4. IP3Rs interact locally with mitochondria. A: electron microscopy image illustrating multiple mitochondria ensheathed by the SR network in a tracheal SMC. Scale bar ⫽ 200 nm. Reproduced from Dai et al. (41) by copyright permission (2011) from Elsevier. B: signaling pathways by which IP3Rs regulate mitochondrial Ca2⫹ concentration ([Ca2⫹]mito), mitochondrial reactive oxygen species (ROS) generation, NF-B activity, and CaV1.2 channel gene expression in arterial SMCs. IP3Rmediated SR Ca2⫹ release activates NF-B both by elevating mitochondrial ROS and via a secondary mitochondria-independent pathway, leading to CaV1.2 gene expression. ETC, mitochondrial electron transport chain. AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 tion of RyRs and local signaling to IP3Rs and plasma membrane ion channels in SMCs. Mitochondria. Spatial localization of mitochondria nearby the SR permits local signaling between these two organelles. Given their local proximity, SR Ca2⫹ release can alter local mitochondrial activity and mitochondria can feedback to regulate nearby SR Ca2⫹ channels. IP3R REGULATION OF MITOCHONDRIAL CA2⫹ CONCENTRATION. In airway and vascular SMCs, mitochondria are located near the SR membrane and IP3R activation elevates mitochondrial Ca2⫹ concentration ([Ca2⫹]mito) (Fig. 3B and 4A) (41, 50, 66, 137, 146, 162, 169, 176, 203). In tracheal SMCs, ⬃99% of mitochondria were within 30 nm of the SR membrane and ⬃82% of mitochondria were ensheathed by the SR (Fig. 4A) (41). Such close spatial proximity between mitochondria and SR enables local Ca2⫹ signaling between these two organelles in SMCs (41). The mitochondrial Ca2⫹ uniporter, the major mitochondrial Ca2⫹ uptake pathway, is sensitive to micromolar Review H2198 IP3Rs IN SMOOTH MUSCLE CELLS nearby mitochondria to control [Ca2⫹]mito and mitochondrial ROS generation. In A10 cells and cultured aortic SMCs, agonist-induced [Ca2⫹]mito elevations measured using targeted aequorin closely matched the kinetics of [Ca2⫹]i transients (175, 203). In contrast, in noncultured aortic and pulmonary artery SMCs, agonist- and IP3-induced [Ca2⫹]mito elevations outlasted [Ca2⫹]i transients by minutes (50, 66). These data suggest that changes in [Ca2⫹]i and [Ca2⫹]mito are not always synchronous and that mitochondria may retain Ca2⫹ in SMCs. The variability in results may also reflect experimental differences in the mitochondrial Ca2⫹ indicator used, protocol, or effects of cell culture. MITOCHONDRIAL REGULATION OF IP3R-MEDIATED CA2⫹ RELEASE. IP3Rs and Intracellular Ca2⫹ Signals in SMCs IP3R activation generates a wide variety of Ca2⫹ signals in SMCs, including flashes, puffs, oscillations, ripples, sparks, waves, and global [Ca2⫹]i (13, 26, 90, 144, 254). Other Ca2⫹ channels, including nonselective cation, RyR, TRP, SOCE, and voltage-dependent Ca2⫹ channels, also contribute to these events in certain SMC types. The following section will discuss IP3Rdependent Ca2⫹ signals and the modulation of these Ca2⫹ signals by other Ca2⫹ channels in SMCs. Properties, cell types, contributing Ca2⫹ channels, and physiological functions of IP3R-regulated Ca2⫹ signals in SMCs are summarized in Table 2. Ca2⫹ puffs. Ca2⫹ puffs arise from the synchronous opening of ⬃30 IP3R channels distributed within a ⬃400-nm diameter cluster in Xenopus oocytes (170, 194). Ca2⫹ puffs correspond to a Ca2⫹ current of 11–23 pA, with a Ca2⫹ current of ⬃0.4 pA per IP3R (170, 194). In SMCs, Ca2⫹ puffs occur due to IP3Rmediated SR Ca2⫹ release, with a minor contribution from AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Mitochondria regulate SMC IP3Rs through multiple mechanisms, including buffering local and global [Ca2⫹]i, controlling ATP synthesis and ROS signaling, and by modulating other ion channels that control membrane potential and [Ca2⫹]i (31, 35, 57, 105, 134, 137, 164, 175, 176, 201–203). Inhibition of mitochondrial Ca2⫹ uptake and oxidative metabolism attenuated IP3R-mediated Ca2⫹ transients in colonic, gallbladder, cultured aortic, and tail artery SMCs (11, 137, 164, 202, 203). These data suggested that mitochondria directly modulate IP3R activity and, in turn, influence generation and propagation of Ca2⫹ signals in SMCs (137, 203). It has been proposed that in SMCs, mitochondrial Ca2⫹ uptake may decrease [Ca2⫹]i nearby IP3Rs, resulting in a reduction in Ca2⫹-dependent inhibition, thereby stimulating further Ca2⫹ release (137, 203). ATP enhances IP3R IP3 and Ca2⫹ sensitivity and is required for SERCA activity in SMCs (57, 105, 134). Thus mitochondria may control SMC IP3R activity and Ca2⫹ release indirectly through ATP generation. Mitochondrial ROS and redox potential may also modulate SMC IP3R expression and activity, thereby influencing IP3R-mediated Ca2⫹ release (31, 201). In vascular SMCs, mitochondria regulate the activity of several plasma membrane ion channels, including voltage-dependent Ca2⫹, Ca2⫹-activated K⫹ (KCa), Ca2⫹-activated Cl⫺ (ClCa), and SOCE channels (175). Mitochondrial modulation of these channels will influence membrane potential and also feedback to alter local and global Ca2⫹ signals, thereby indirectly influencing SMC IP3R channel activity. Therefore, mitochondrial regulation of IP3Rs in SMCs involves several integrated signaling pathways. RyRs. In colonic SMCs, purinergic receptor stimulation elevated Ca2⫹ puff frequency and amplitude, which was attenuated by both xestospongin C (XeC), an IP3R blocker, and ryanodine, indicating involvement of both IP3Rs and RyRs (14). However, ryanodine and an anti-RyR antibody did not alter spontaneous and ACh-induced Ca2⫹ puffs in ureteric SMCs, suggesting that IP3R activation alone can also generate these Ca2⫹ transients (26). Similarly, in guinea pig colonic SMCs, localized photolysis of IP3 generated Ca2⫹ puffs, which were abolished by 2-aminoethoxydiphenyl borate, an IP3R inhibitor (164). Thus Ca2⫹ puffs are stimulated by IP3R activation, with RyRs contributing in certain SMC types. Clustering of IP3Rs on the SR membrane has been proposed to be essential for Ca2⫹ puff generation in SMCs (26, 62, 91, 164). Consistent with this conclusion, IP3R clustering and Ca2⫹ puffs were observed in colonic and ureteric SMCs but neither were detected in portal vein and pulmonary artery SMCs (26, 62, 91, 164). The physiological functions of Ca2⫹ puffs in SMCs have not been identified. Ca2⫹ flashes. Spontaneous, rapid [Ca2⫹]i events termed “Ca2⫹ flashes” were observed during rhythmic phasic contractions of unstimulated gallbladder SMCs (13). Ca2⫹ flash frequency was reduced by inhibiting voltage-dependent Ca2⫹ channels, IP3Rs, and RyRs, suggesting that all these channels contribute to these Ca2⫹ signals in SMCs (13). In contrast, in mesenteric artery and urinary bladder SMCs, Ca2⫹ flashes induced by electrical field stimulation were unaltered by depleting SR Ca2⫹, indicating that IP3Rs and RyRs do not generate these signals in certain SMC types (104, 157). Ca2⫹ flashes also occurred in ⬃2% of resting tail artery SMCs but such low occurrence prevented detailed study of the contribution of IP3Rs to these events (9). Ca2⫹ oscillations. Ca2⫹ oscillations are repetitive, nonpropagating global [Ca2⫹]i elevations generated by periodic, pulsatile release of SR Ca2⫹ in SMCs (10, 18, 22, 29, 111). Ca2⫹ oscillations occur due to cyclical positive and negative feedback of [Ca2⫹]i on IP3R channel activity with contributions from RyRs and TRPC channels (10, 18, 29, 111, 190). In isolated retinal arteriole SMCs, ET-1 increased Ca2⫹ oscillation frequency and this elevation was inhibited by blockers of IP3Rs and RyRs, indicating that IP3R-RyR cross talk stimulates Ca2⫹ oscillations (190, 218). Ca2⫹ oscillations in A7r5 cells required both IP3R1-mediated SR Ca2⫹ release and TRPC6 as a receptor-operated Ca2⫹ influx pathway (111). In airway SMCs, IP3R inhibition reduced Ca2⫹ oscillation frequency, leading to relaxation (10, 18). Similarly, in basilar artery SMCs, IP3R-mediated Ca2⫹ oscillations activated ClCa channels, leading to depolarization, Ca2⫹ influx, and vasoconstriction (67). These studies suggested that IP3R-dependent Ca2⫹ oscillations induce SMC contraction. In contrast, agonist-induced IP3R-mediated Ca2⫹ oscillations in mesenteric artery SMCs did not contribute Ca2⫹ for vasoconstriction (144). Thus the physiological functions of Ca2⫹ oscillations in some SMC types remain poorly understood. Ca2⫹ ripples. Ca2⫹ ripples are spontaneous, low amplitude, propagating, IP3R-mediated Ca2⫹ signals that have been observed in unstimulated aortic, mesenteric, and tail artery SMCs (9, 249). Ca2⫹ ripples occur due to PLC activation and SR Ca2⫹ release that may be due to IP3Rs in tail artery SMCs (9). Future studies would need to be performed using alternative approaches, including selective IP3R antagonists and IP3R Review H2199 IP3Rs IN SMOOTH MUSCLE CELLS Table 2. SMC Ca2⫹ signals regulated directly or indirectly by IP3Rs Ca2⫹ Signal 2⫹ Properties SMC Type Additional Ca2⫹ Channels Involved Physiological Function 0.02–0.04 Hz/cell 1.13–2.02 57–160 ms 107–250 ms 1.89–2.51 m Colon (14, 164), renal artery (91), ureter (26) RyR (14, 91, 164) Unclear Ca2⫹ flash Frequency: Amplitude*: Rise time: t1/2 decay: 0.2–0.5 Hz/cell 1.5–2.6 0.2–0.8 s 0.5–1.5 s Gallbladder (13) RyR, voltage-dependent Ca2⫹ (13) Contraction (13) Ca2⫹ oscillation Frequency: Amplitude*: Rise time: t1/2 decay: 0.07–0.4 Hz/cell 1.1–6.5 2–6 s 3–18 s A7r5 cells (111), airway (10, 18), basilar artery (67), mesenteric artery (144), retinal arteriole (190, 218) RyR (218), TRPC6 (111) Contraction (10, 18, 67) Ca2⫹ ripple Frequency: Amplitude*: Rise time: t1/2 decay: Velocity†: 0.05–0.19 Hz/cell 1.05-1.8 1–2 s 4–6 s ⬃18 m/s Aorta (9), mesenteric artery (249), tail artery (9) Ca2⫹ spark Frequency: Amplitude*: Rise time: t1/2 decay: Spatial spread: 0.07–0.59 Hz/cell 1.34–2.05 10–65 ms 30–150 ms 0.52–4.7 m Choroidal and retinal arterioles (190, 218), pulmonary artery (252), trachea (116), vas deferens (233) RyR (116, 190, 218, 233, 252) Contraction (190, 218) Ca2⫹ wave Frequency: Amplitude*: Rise time: t1/2 decay: Spatial spread: Velocity†: 0.04–1.41 Hz/cell 1.4–6.9 0.5–2 s 2–10 s 8.8–50 m 7–126 m/s Cerebral artery (60, 61, 88, 89, 151, 156, 234, 254), choroidal and retinal arteriole (190), cremaster artery and arteriole (177, 231), mesenteric artery (86, 104, 133, 249), pulmonary artery (76, 219), tail artery (49, 81), airway (17), cecum (70, 82), colon (15, 70, 117, 135, 136), duodenum (28), gallbladder (12), ileum (167), inferior vena cava (42, 107, 108, 184), portal vein (25, 28, 62, 145), trachea (94, 103, 179), ureter (26), urinary bladder (157) Na⫹/Ca2⫹ exchanger (107, 108), nonselective cation (42), RyR (12, 17, 25, 28, 62, 70, 81, 88, 94, 145, 151, 179, 184, 231), SOCE (107, 108), voltagedependent Ca2⫹ (12, 42, 60, 70, 88, 107, 108, 179) Contraction (17, 28, 42, 49, 70, 76, 103, 104, 107, 108, 133, 151, 184, 231, 249), gene expression (60), mitochondrial ROS generation (156), proliferation (234), relaxation (15) Global [Ca2⫹]i Amplitude: ⬃30–685 nM Aorta (206, 220), cerebral artery (2, 60, 61, 67, 71, 88, 89, 151, 156, 237), choroidal arteriole (190), cremaster artery and arteriole (177, 231), femoral artery (99), mesenteric artery (86, 104, 133, 249, 250), pulmonary artery (27, 76, 87, 91, 98, 160, 180, 219, 235), renal artery (91), retinal arteriole (190, 218), tail artery (9, 49, 81), airway (17, 115, 128), cecum (70, 82), colon (15, 70, 102, 117, 135, 136, 164), ileum (167), iliac lymph vessels (121), inferior vena cava (42, 107, 108, 184), portal vein (25, 28, 62, 114, 145), prostate (54), small intestine (96, 122), trachea (94, 103), ureter (26), vas deferens (233) Nonselective cation (15, 42), RyR (17, 27, 28, 54, 67, 70, 71, 81, 86–88, 91, 94, 96, 115, 145, 151, 184, 190, 218, 219, 231, 235), SOCE (98, 107, 108, 114, 160, 177, 180, 220, 250), TRPC1 (206), TRPC3 (2, 237), TRPM4 (61), voltage-dependent Ca2⫹ (2, 42, 60, 61, 67, 70, 71, 76, 88, 96, 107, 108, 237) Contraction (2, 9, 15, 17, 27, 28, 42, 49, 54, 67, 70, 71, 76, 86, 87, 96, 99, 102104, 107, 108, 115, 121, 122, 128, 133, 151, 160, 167, 177, 180, 184, 190, 218, 231, 235, 237, 249, 250, 254), gene expression (60) puff Contraction (9, 249) ROS, reactive oxygen species; RyR, ryanodine-sensitive Ca2⫹ release channels; SOCE, store-operated Ca2⫹ entry; TRPC, transient receptor potential canonical. *F/F0. †Propagation velocity. knockdown, to confirm that Ca2⫹ ripples occur due to IP3Rmediated Ca2⫹ release in SMCs. In SMCs of pressurized mesenteric arteries, Ca2⫹ ripples were observed only after the development of myogenic tone (249). Similarly, ANG II receptor antagonists abolished Ca2⫹ ripples and reduced myogenic tone in tail arteries (9). It was concluded that ANG II produced locally within the arterial wall stimulates Ca2⫹ rip- ples, which regulate myogenic tone (9). Therefore, IP3Rmediated Ca2⫹ ripples may be a Ca2⫹ signal by which the local renin-angiotensin system in the arterial wall contributes to myogenic constriction (9, 249). Ca2⫹ sparks. Ca2⫹ sparks are localized, intracellular Ca2⫹ transients that occur due to the concerted opening of several spatially localized RyRs (37, 90, 159). RyR-mediated Ca2⫹ AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 Frequency: Amplitude*: Rise time: t1/2 decay: Spatial spread: Ca Review H2200 IP3Rs IN SMOOTH MUSCLE CELLS and arterioles, suggesting that IP3Rs contribute to these signals in these SMC types (12, 15, 62, 70, 219, 231, 249). Basal release of receptor ligands by endothelial cells and circulating receptor agonists may also stimulate Gq/PLC-mediated IP3 generation in SMCs, leading to spontaneous IP3R-mediated Ca2⫹ waves (61, 156). However, in cerebral artery SMCs, neither 50% knockdown of IP3R1 or XeC altered baseline Ca2⫹ wave frequency, suggesting that IP3Rs do not contribute to the generation of spontaneous Ca2⫹ waves in all SMC types (254). Thus the contribution of IP3Rs to spontaneous Ca2⫹ waves that occur in the complete absence of agonists in vascular SMCs is unclear. Ligands that bind to PLC-coupled receptors enhanced Ca2⫹ wave generation in several SMC types, including cerebral, mesenteric, pulmonary, and tail arteries, cecum, colon, duodenum, gallbladder, ileum, trachea, inferior vena cava, portal vein, and ureter (12, 26, 28, 42, 49, 76, 82, 103, 104, 135, 167, 254). IP3R inhibitors, anti-IP3R antibodies, and IP3R knockdown attenuated agonist-induced Ca2⫹ waves, indicating that IP3R activation is essential for generation of these Ca2⫹ signals (17, 25, 26, 28, 42, 60, 62, 70, 76, 94, 104, 156, 157, 254). Thapsigargin, ryanodine, and anti-RyR antibodies also inhibited agonist-induced Ca2⫹ waves in certain SMCs, suggesting that RyRs may also contribute to these events (17, 25, 27, 28, 62, 70, 81, 94, 104, 151, 179, 184). Therefore, IP3Rs and RyRs can both influence the generation of spontaneous and agonist-induced Ca2⫹ waves, with relative involvement of each appearing to vary in different SMC types. The contribution of IP3Rs and RyRs to the propagation of Ca2⫹ waves has also been examined in SMCs (28, 62, 135, 184, 231). In colonic SMCs, carbachol and IP3 photolysis stimulated local SR Ca2⫹ release, which transformed into a propagating Ca2⫹ wave only in the presence of cytosolic Ca2⫹ Fig. 5. IP3R-mediated Ca2⫹ waves in SMCs of different tissues. Images illustrate Ca2⫹ waves induced by endothelin-1 (ET-1) in cerebral artery SMCs (A), spontaneously in tail artery SMCs (B), by IP3 photolysis in a colonic SMC (C), and spontaneously in gallbladder SMCs (D). Traces corresponding to changes in [Ca2⫹]i over time as determined in regions highlighted by boxes or regions in confocal images are also shown. White boxes in A indicate regions where Ca2⫹ sparks occurred (not shown). Reproduced with copyright permission (2012): Narayanan et al. (156) from Wolters Kluwer Health (A), Dreja et al. (49) from John Wiley and Sons (B), McCarron et al. (136) from the American Society for Biochemistry and Molecular Biology (C), and Balemba et al. (12) from the American Physiological Society (D). AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 sparks have been described in SMCs of a wide variety of tissues, including arteries, arterioles, veins, gallbladder, gastric antrum, intestine, trachea, ureter, and urinary bladder (72, 90, 178, 181, 230). IP3Rs have been reported to contribute to Ca2⫹ sparks, albeit in a small number of SMC types (116, 190, 218, 252). RyR- and IP3R-mediated SR Ca2⫹ release both stimulated Ca2⫹ sparks in SMCs of choroidal and retinal arterioles, pulmonary artery, and trachea (116, 190, 218, 252). In contrast, IP3R inhibition elevated Ca2⫹ spark frequency in vas deferens SMCs, although this may have occurred due to an [Ca2⫹]SR elevation (233). Reports (190, 218) in retinal and choroidal arteriole SMCs suggested that IP3R-mediated Ca2⫹ sparks may contribute to global [Ca2⫹]i and contractility. However, whether localized Ca2⫹ sparks directly influence SMC global [Ca2⫹]i is uncertain. Ca2⫹ waves. Ca2⫹ waves are propagating elevations in [Ca2⫹]i that occur due to SR Ca2⫹ release in vascular and nonvascular SMCs (12, 17, 28, 62, 70, 76, 89, 104, 135, 156, 167). The activation of IP3Rs, RyRs, or both channels can control both the generation and propagation of spontaneous and agonist-induced Ca2⫹ waves in SMCs. Figure 5 illustrates IP3R-mediated Ca2⫹ waves imaged in SMCs of vascular and nonvascular tissues. Spontaneous Ca2⫹ wave generation was inhibited by ryanodine in SMCs of cecum, colon, gallbladder, cerebral, cremaster and pulmonary arteries, and portal vein, suggesting that RyRs contributed to these events (12, 62, 70, 88, 151, 219, 231). Caffeine stimulated Ca2⫹ waves, supporting the view that RyR activation alone can generate Ca2⫹ waves in SMCs (70, 71, 145, 184). In contrast, IP3R blockers reduced spontaneous Ca2⫹ waves in SMCs of cecum, colon, gallbladder, portal vein, pulmonary, mesenteric, and cremaster feed arteries Review IP3Rs IN SMOOTH MUSCLE CELLS have also suggested that IP3Rs do not regulate global [Ca2⫹]i in certain SMC types (88, 144, 157, 254). In mesenteric, cerebral artery, and urinary bladder SMCs, IP3R-mediated Ca2⫹ waves and oscillations did not elevate global [Ca2⫹]i. Tissue-specific variability in IP3R modulation of global [Ca2⫹]i could be due to multiple factors, including differences in the amplitude of Ca2⫹ signals generated, activation and contribution of other Ca2⫹ channels, and regulation of IP3R activity by tissue-specific proteins. In summary, IP3R activation, sometimes with the involvement of other Ca2⫹ channels, produces a wide variety of intracellular Ca2⫹ signals, which control several physiological functions in SMCs. IP3R Regulation of SMC Physiological Functions IP3Rs regulate SMC physiological functions, including contractility, gene expression, migration, and proliferation (Table 2). IP3R control of these functions can occur via the modulation of intracellular Ca2⫹ signals and via local communication with ion channels and organelles. Contractility. IP3R-mediated SR Ca2⫹ release stimulates contraction in both vascular and nonvascular SMCs. In gallbladder SMCs, IP3R activation contributed to Ca2⫹ flashes and action potentials that preceded rhythmic contractions of individual smooth muscle bundles (13). IP3R-mediated Ca2⫹ oscillations induced airway and basilar artery contraction (10, 18, 67). Ca2⫹ sparks generated by IP3R and RyR activation contributed to vasoconstriction in retinal and choroidal arterioles (190, 218). Reports in mesenteric, pulmonary, and tail arteries, inferior vena cava, and portal vein proposed that IP3R-mediated Ca2⫹ waves directly induce vasoconstriction (28, 42, 49, 76, 86, 104, 107, 108, 133, 184, 249). XeC inhibited agonistinduced contraction in iliac lymph vessels, pulmonary arteries, and small femoral artery branches, indicating that agonists induce vasoconstriction through IP3R activation (87, 99, 121, 128, 235). Similarly, in nonvascular SMCs of ileum, prostate, small intestine, and trachea, IP3R blockers inhibited spontaneous and agonist-induced contraction (54, 103, 122, 167). In airway and intestinal SMCs, membrane depolarization activated IP3Rs and RyRs, which contributed to contraction (17, 70, 96, 115). Collectively, IP3R-mediated Ca2⫹ release regulates spontaneous and agonist-induced contraction of vascular and nonvascular SMCs. IP3R activation and the resulting SR Ca2⫹ store depletion also stimulated SOCE channel-dependent Ca2⫹ influx, which induced contraction of SMCs of aorta, inferior vena cava, cremaster, and pulmonary arteries (107, 108, 160, 177, 220, 250). IP3R activation has also been reported to induce relaxation of certain SMC types (15, 102). In colonic SMCs, IP3R-mediated Ca2⫹ release stimulated KCa channels, resulting in spontaneous transient outward currents, hyperpolarization, and relaxation (15, 102). However, in urinary bladder SMCs, electrical field stimulation enhanced Ca2⫹ waves, which did not induce contraction (157), suggesting that IP3Rs do not control contractility in certain SMC types. IP3R regulation of pressure-induced myogenic vasoconstriction has been examined in several vascular beds. U-73122, a PLC inhibitor, dilated pressurized cerebral and ophthalmic arteries, suggesting that DAG/PKC and/or IP3/IP3Rs contribute to myogenic tone (85, 92, 166, 237). Inhibitors of PLC or IP3Rs attenuated Ca2⫹ waves and dilated pressurized cremaster muscle feed arteries and arterioles, suggesting that IP3R-de- AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 and a steady [IP3]i (135). This study indicated that IP3R activation alone is sufficient for propagation of these Ca2⫹ signals in SMCs. An alternative concept of Ca2⫹ wave progression suggests that IP3R-mediated Ca2⫹ release initiates a Ca2⫹ wave in SMCs, which then propagates exclusively due to RyR-dependent CICR (28, 62, 184). RyR contribution to Ca2⫹ wave propagation has been examined primarily by using ryanodine to inhibit these channels (28, 62, 184). However, ryanodine may inhibit Ca2⫹ wave propagation by depleting SR Ca2⫹ and not solely by blocking RyRs (81, 86, 117, 136, 151). In contrast, tetracaine, which blocks RyRs without depleting SR Ca2⫹, attenuated spontaneous Ca2⫹ waves in SMCs of cremaster feed arteries, suggesting that RyRs can regulate Ca2⫹ wave propagation in certain SMC types (231). Studies have proposed that Ca2⫹ influx via membrane proteins, including the Na⫹/Ca2⫹ exchanger, nonselective cation channels, SOCE channels, and voltage-dependent Ca2⫹ channels, also contributes to Ca2⫹ wave propagation and maintenance in certain SMC types (12, 42, 60, 70, 88, 107, 108, 179). In summary, IP3Rs contribute to Ca2⫹ wave generation and propagation in SMCs. Evidence, obtained in many cases by using nonspecific pharmacological tools, also suggests that RyRs and other Ca2⫹ channels regulate Ca2⫹ wave propagation in some SMC types. Global [Ca2⫹]i. Global [Ca2⫹]i is spatially averaged cytosolic [Ca2⫹]i. An elevation in global [Ca2⫹]i induces contraction, whereas a reduction in global [Ca2⫹]i results in relaxation (22, 29, 90). IP3R activation elevates SMC global [Ca2⫹]i directly, through SR Ca2⫹ release and indirectly, by stimulating Ca2⫹ influx via plasma membrane-localized ion channels. IP3R-mediated SR Ca2⫹ release elevates global [Ca2⫹]i in a wide variety of different SMC types (Table 2). IP3R activation stimulated plasma membrane-localized TRPC1, TRPM4, and voltage-dependent Ca2⫹ channels, leading to Ca2⫹ influx and global [Ca2⫹]i elevation in basilar, cerebral artery, and aortic SMCs (61, 67, 206). In cerebral artery SMCs, physical coupling of IP3R1 to TRPC3 channels results in membrane depolarization and an indirect elevation in global [Ca2⫹]i via voltage-dependent Ca2⫹ channel activation (2). In SMCs of aorta, mesenteric, and pulmonary arteries, cremaster arterioles, inferior vena cava, and portal vein, IP3R-mediated SR Ca2⫹ depletion activated SOCE, leading to a global [Ca2⫹]i elevation (98, 107, 108, 114, 160, 177, 180, 220, 250). Collectively, these studies indicate that IP3R activation can elevate global [Ca2⫹]i directly, through SR Ca2⫹ release and indirectly, through stimulation of plasma membrane ion channel-dependent Ca2⫹ influx in SMCs. The relative contribution of IP3R-mediated SR Ca2⫹ releasedependent and -independent mechanisms to global [Ca2⫹]i elevations was examined in cerebral artery SMCs (237). SR Ca2⫹ depletion reduced IP3-induced global [Ca2⫹]i elevation by ⬃25%, suggesting that the contribution of IP3R-mediated SR Ca2⫹ release to global [Ca2⫹]i is minor (237). TRPC3 knockdown reduced IP3-induced global [Ca2⫹]i elevation by ⬃70%, indicating that IP3R physical coupling to TRPC3 channels and the resulting plasma membrane Ca2⫹ influx are responsible for the majority of the global [Ca2⫹]i elevation (237). Therefore, IP3R-mediated Ca2⫹ release can make a minor direct contribution to global [Ca2⫹]i, with IP3R control of membrane potential and Ca2⫹ influx being prominent indirect mechanisms by which IP3Rs influence global [Ca2⫹]i. Reports H2201 Review H2202 IP3Rs IN SMOOTH MUSCLE CELLS and upregulation of all three IP3R isoforms in mesenteric artery SMCs (3, 20). Consistent with these observations, Ca2⫹ wave frequency was elevated in proliferating cerebral artery SMCs (234). PLC and IP3R antagonists attenuated Ca2⫹ waves and proliferation in cerebral artery SMCs, indicating that IP3Rmediated Ca2⫹ release stimulates proliferation (234). Similarly, in cultured aortic SMCs, IP3R-dependent intercellular Ca2⫹ waves promoted proliferation and migration (149). An elevation in IP3R-mediated Ca2⫹ release also stimulated proliferation of cultured preglomerular microvascular SMCs (36). XeC inhibited pulsatile pressure-induced aortic SMC migration, and IP3R1 knockdown reduced A7r5 cell proliferation (205, 228). Taken together, these findings provide strong evidence that IP3R activation stimulates SMC migration and proliferation. IP3Rs and SMC Pathologies Vascular SMC diseases. Vascular SMC IP3R expression, [IP3]i, and Ca2⫹ signaling are altered in several diseases, including hypertension, atherosclerosis, and diabetes-related vascular complications (19, 125, 130, 138, 192, 193, 236). Genetic hypertension in rats is associated with elevations in both [IP3]i and IP3R IP3-binding affinity in SMCs. Basal and phenylephrine-induced [IP3]i were both higher in cultured aortic SMCs of spontaneously hypertensive rats than Wistar-Kyoto controls (236). A [3H]IP3 binding assay indicated that the IP3-binding capacity of IP3Rs was significantly higher in aortic SMCs of spontaneously hypertensive rats compared with Wistar-Kyoto rats (19). Although myogenic tone and global [Ca2⫹]i are higher in vascular SMCs of hypertensive rats, compared with normotensive controls (92), altered vascular SMC IP3R expression and Ca2⫹ signaling have not been reported. During the pathogenesis of atherosclerosis, vascular SMCs are exposed to oxidized LDL, which stimulates plaque formation (130). In aortic SMCs exposed to oxidized LDL and in atherosclerotic aorta, IP3R1 protein and IP3R-dependent Ca2⫹ release were reduced (125, 130). SERCA2b expression was also downregulated in atherosclerotic aorta, suggesting that an [Ca2⫹]SR reduction may also contribute to the impaired IP3Rmediated Ca2⫹ release in atherosclerosis (125, 130). Diabetes-related vascular complications are associated with a reduction in IP3R expression and Ca2⫹ release in SMCs of aorta and glomerular arterioles (138, 192, 193). In renal glomerular arteriolar SMCs of diabetic rats, IP3R protein was lower than in nondiabetic controls (138). Protein expression of all three IP3R isoforms and IP3R-mediated [Ca2⫹]i signals were attenuated in aortic SMCs of genetic and inducible animal models of diabetes (192). High glucose reduced IP3R protein in A7r5 cells, suggesting that a diabetes-induced reduction in vascular SMC IP3R levels may be due to direct effects of hyperglycemia (192). IP3R1 protein and IP3R-mediated [Ca2⫹]i elevations were reduced, and TGF-2 levels were elevated in diabetic rat aorta (193). Intraperitoneal administration of an anti-TGF- antibody partly restored IP3R1 expression and IP3R-mediated [Ca2⫹]i elevations in aortic and glomerular arteriolar SMCs and prevented the development of glomerular hypertrophy (138, 193). These reports suggested that TGF-induced suppression of IP3R expression underlies vascular dysfunction, leading to diabetic glomerular hypertrophy. Collectively, these studies indicate that an alteration in IP3R AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 pendent Ca2⫹ waves regulate myogenic tone in these vessels (231). Similarly, in pressurized mesenteric and tail arteries, IP3R-mediated Ca2⫹ ripples were proposed to stimulate myogenic constriction (9, 249). SR-dependent Ca2⫹ waves contributed to myogenic tone at low intravascular pressure in cerebral artery SMCs, although the contribution of IP3Rs was not determined (151). These studies suggest that IP3R-mediated Ca2⫹ release regulates the myogenic response. In contrast, in pressurized mesenteric and cerebral arteries, IP3R-dependent Ca2⫹ oscillations and waves did not contribute significantly to myogenic vasoconstriction (88, 144, 254). Explanations for these different observations include that the frequency and amplitude of IP3R-mediated Ca2⫹ signals are likely to be important factors that determine functional impact on contractility. In addition, the activation status of other signaling pathways that may enhance the sensitivity of the contractile apparatus to IP3R-induced Ca2⫹ release is also likely to modify functional responses. IP3Rs also control arterial SMC contractility via an SR Ca2⫹ release-independent mechanism that involves physical coupling to plasma membrane TRPC3 channels (Fig. 3C) (1, 2, 237, 254). In cerebral arteries at physiological intravascular pressure, the majority (⬃60%) of IP3-induced vasoconstriction occurred through IP3R1-TRPC3 physical coupling, with a minor contribution from IP3R-mediated SR Ca2⫹ release (237). At low intravascular pressure, where [Ca2⫹]SR is low and the driving force for cation influx is high, IP3R1-TRPC3 physical coupling fully accounted for IP3-induced vasoconstriction (237). Thus, in cerebral artery SMCs, IP3Rs induce contraction primarily via an SR Ca2⫹ release-independent mechanism that involves TRPC3 channel activation. In summary, SMC contractility regulation by IP3Rs appears to be tissue and stimulus dependent. Contrary to what was previously a prevailing view, IP3R-mediated Ca2⫹ release induces contraction in some, but not all, SMC types, with IP3R activation also stimulating contraction via SR Ca2⫹ release-independent mechanisms. Gene expression. IP3R-mediated Ca2⫹ release can activate transcription factors, thereby regulating gene expression in SMCs (40, 51, 60, 156). In cerebral artery SMCs, IP3Rmediated SR Ca2⫹ release activated NF-B both directly and indirectly, by stimulating mitochondrial ROS production (Fig. 4B) (156). IP3R-dependent NF-B activation stimulated CaV1.2 channel ␣1C subunit gene expression, leading to vasoconstriction (156). NF-B p105/p50 subunit expression was also upregulated by IP3R-mediated SR Ca2⫹ release via a mitochondrial ROS- and NF-B-independent pathway (156). In cerebral artery and cultured aortic SMCs, IP3R-dependent SR Ca2⫹ release stimulated nuclear factor of activated T-cell c3, a transcription factor that can downregulate KCa channel 1subunit and Kv2.1 channel expression (8, 60, 113, 161). IP3Rmediated Ca2⫹ release also activated cAMP response elementbinding protein, a Ca2⫹-dependent transcription factor, in SMCs of cerebral arteries and the portal vein (40, 51). Therefore, Ca2⫹ released by IP3Rs modulates multiple transcription factors that can control ion channel gene expression in SMCs. Migration and proliferation. Vascular SMCs proliferate and migrate during vasculogenesis and in response to injury and are associated with elevated IP3R expression and Ca2⫹ release (3, 20, 149, 205, 228, 234). Proliferation correlated with an elevation in IP3R1 expression in aortic and carotid artery SMCs Review IP3Rs IN SMOOTH MUSCLE CELLS insulin resistance, and diet-induced diabetes (243). A report (200) that examined SMC function in IP3R1⫺/⫺ mice determined that gastric SMCs exhibited irregular bursts of spike potentials, resulting in reduced contractility. Population analysis studies have identified human diseases caused by IP3R gene mutations. Similar to observations in knockout mice, there is a strong correlation between IP3R gene mutations and neurological disease. A heterozygous deletion and a mutation in the IP3R1 gene have been identified in patients with spinocerebellar ataxia and tremors (68, 221). SMC pathologies have not been reported that are associated with deletions or mutations in IP3R genes. Recent studies (75, 165) reported that single nucleotide polymorphisms in genes encoding IP3R3 and IP3 3-kinase C, which phosphorylates IP3 to IP4, predisposed children with Kawasaki disease, a pediatric systemic vascular autoimmune disease, to coronary artery aneurysms. Summary Since the discovery of IP3Rs more than 20 years ago, research has identified these proteins as SR-located ion channels that are expressed in virtually all cell types. In SMCs, IP3R Fig. 6. IP3R signaling in SMCs. Illustrated are the following: pathways controlling IP3R cellular expression (A), regulators of IP3R channel activity (B), ion channels and organelles that communicate with IP3Rs (C), Ca2⫹ signals generated by IP3R-mediated Ca2⫹ release (D), and physiological functions modulated by IP3Rs (E). AP-2, activator protein 2; RyR, ryanodine-sensitive Ca2⫹ release channels; CREB, cAMP response element-binding protein; NFATc3, nuclear factor of activated T-cell c3; RACK, receptor for activated PKC 1; FKBP12, 12-kDa FK506 binding protein. AJP-Heart Circ Physiol • doi:10.1152/ajpheart.01146.2011 • www.ajpheart.org Downloaded from http://ajpheart.physiology.org/ by 10.220.33.3 on October 16, 2016 expression and IP3R-mediated Ca2⫹ signaling in vascular SMCs contributes to the pathogenesis of vascular diseases. Asthma. Asthma is associated with enhanced SMC [IP3]i, IP3R signaling, and contractility, leading to airway hyperresponsiveness and remodeling (132, 209). In Fisher rats, an asthmatic animal model, IP3-5-phosphatase expression and activity were both reduced, leading to elevations in [IP3]i and IP3R-mediated Ca2⫹ release in airway SMCs (209). This enhanced IP3-induced Ca2⫹ release may underlie airway SMC hyperresponsiveness in asthma (209). 2-Aminoethoxydiphenyl borate inhibited acidic pH-induced remodeling of airway SMCs, suggesting that IP3Rs may also regulate extracellular matrix formation and airway remodeling in asthma (132). Pathologies associated with IP3R gene deletion and mutation. Studies performed in IP3R knockout (IP3R⫺/⫺) mice have provided valuable information regarding pathologies associated with these proteins, although limited information is available regarding SMC dysfunction. IP3R1⫺/⫺ mice are rarely born alive, indicating that IP3R1 is crucial for embryonic development (131). Animals that survive exhibit severe neurological pathologies, including ataxia and epilepsy (131). IP3R1⫹/⫺ mice displayed increased susceptibility to glucose intolerance, H2203 Review H2204 IP3Rs IN SMOOTH MUSCLE CELLS Future Directions This review has summarized studies investigating IP3R expression, cellular localization, activity, Ca2⫹ signals generated, physiological functions regulated, and associated pathologies in SMCs. There are still major questions that remain regarding IP3R functionality in SMCs. Studies are necessary to better determine mechanisms that regulate IP3R gene transcription and protein expression in SMCs. IP3R signaling in non-SMCs is modulated by a wide variety of proteins, including calmodulin, Ca2⫹-binding protein 1, Ca2⫹- and integrin-binding protein 1, chromogranins, ERp44, IP3R-binding protein released with IP3, and G␥ (57, 212). Modulation of IP3R signaling by these proteins should be examined in SMCs. Studies should also be aimed at determining other cellular organelles and ion channels that interact with IP3Rs in SMCs. A better understanding of the contribution of RyRs and other Ca2⫹ channels to IP3R-mediated Ca2⫹ signals in SMCs is also needed. Research is required to elucidate mechanisms that underlie tissuespecific variability in IP3R signaling in SMCs. Studies would benefit from the availability of novel, selective, high-affinity, membrane-permeant IP3R antagonists to investigate IP3R signaling, physiological functions, and pathological alterations. SMC-specific IP3R animal models, including those that induce knockout, express IP3R mutations associated with human diseases, or alter known IP3R coupling domains, would also provide the capability to investigate the contribution of these proteins to physiological functions and pathological alterations both in vivo and in vitro. SMC dysfunctions in IP3R knockout mice also need to be examined. Screening of humans to identify potential IP3R mutations associated with SMC diseases is also necessary. ACKNOWLEDGMENTS We thank Drs. John Bannister, Sarah Burris, and Charles Leffler for critical reading of the manuscript. GRANTS This work was supported by National Heart, Lung, and Blood Institute Grants HL-67061, HL-110347, and HL-094378 (to J. H. Jaggar) and K01-HL096411 (to A. Adebiyi). DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: D.N. prepared figures; D.N., A.A., and J.H.J. drafted manuscript; D.N., A.A., and J.H.J. edited and revised manuscript; D.N., A.A., and J.H.J. approved final version of manuscript. REFERENCES 1. Adebiyi A, Narayanan D, Jaggar JH. Caveolin-1 assembles type 1 inositol 1,4,5-trisphosphate receptors and canonical transient receptor potential 3 channels into a functional signaling complex in arterial smooth muscle cells. J Biol Chem 286: 4341–4348, 2011. 2. Adebiyi A, Zhao G, Narayanan D, Thomas-Gatewood CM, Bannister JP, Jaggar JH. 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IP3R isoforms, cellular expression, and localization influence channel functions (Fig. 6A). Several endogenous ligands, kinases, and proteins regulate SMC IP3R activity (Fig. 6B). IP3R signaling involves communication with cellular organelles, including mitochondria, RyRs, and plasma membrane ion channels in SMCs (Fig. 6C). IP3R-mediated cellular pathways include both SR Ca2⫹ release-dependent and -independent mechanisms regulated through physical coupling to ion channels and control of SOCE. IP3R-mediated Ca2⫹ release generates a wide variety of local and global Ca2⫹ signals in SMCs (Fig. 6D). IP3R-dependent cellular mechanisms control SMC physiological functions, including contraction, gene expression, migration, and proliferation (Fig. 6E). Diseases of SMC-containing tissues are associated with altered IP3R expression and channel activity. Thus IP3Rs control SMC physiological functions and pathological alterations in IP3R signaling contribute to disease. 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