Inositol trisphosphate receptors in smooth muscle cells

Abstract

Inositol 1,4,5-trisphosphate 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.

Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries

“…TRPC6 and TRPC3 channels are permeant to Na ϩ and Ca 2ϩ , IP 3 R1 is a Ca 2ϩ -selective channel, and TRPM4 is a Na ϩ -selective channel (12,26). Data supporting signaling from TRPC6 to ANO1 include Hyp9 activation of Cl Ϫ currents and blockade of Hyp9 activation of Cl Ϫ currents by both T16Ainh-A01 and selective ANO1 knockdown in myocytes.…”

“…Ca 2ϩ is a principal intracellular activator of ANO1 channels, but the source(s) of Ca 2ϩ that activate ANO1 and ion channels that generate these intracellular Ca 2ϩ signals is unclear (4). Intracellular Ca 2ϩ signals can arise from the opening of plasma membrane Ca 2ϩ -permeant channels, including voltage-dependent Ca 2ϩ and transient receptor potential (TRP) channels and intracellular Ca 2ϩ release from sarcoplasmic reticulum (SR) ryanodine-sensitive Ca 2ϩ release channels and inositol trisphosphate receptors (IP 3 Rs) (12,14,17,26). In cerebral artery myocytes, ANO1 channels are activated by local Ca 2ϩ influx through yet unidentified plasma membrane nonselective cation channels (5).…”

“…Selective ANO1 knockdown attenuated intravascular pressure-induced cerebral artery depolarization and vasoconstriction (5). Cell-specific knockout of ANO1 reduced Cl Ca currents in aortic and cerebral arteriole myocytes, agonist-induced vasoconstriction in retinal and skeletal muscle arterioles, and systemic blood pressure and attenuated hypertension in mice (15) (12,14,17,26). In cerebral artery myocytes, ANO1 channels are activated by local Ca 2ϩ influx through yet unidentified plasma membrane nonselective cation channels (5).…”

Advanced Glycation End Products Impair Ca2+ Mobilization and Sensitization in Colonic Smooth Muscle Cells via the CAMP/PKA Pathway

“…4B). It has been reported that cAMP/PKA phosphorylates IP 3 R3 in SMCs and inhibits IP 3 R3-operated Ca 2+ store release [30]. In addition, cAMP/PKA decreases MLC phosphorylation by inhibiting RhoA, thus activating MLCP [31,32].…”

Theoretical Investigation of Intra- and Inter-cellular Spatiotemporal Calcium Patterns in Microcirculation

“…Recently, Falcke et al (Falcke 2003) (Berridge 1993;Rottingen and Iversen 2000;Berridge and Dupont 1994;Jaffe 2010;Narayanan, Adebiyi, and Jaggar 2012; (Halidi et al 2011;Marchant, Callamaras, and Parker 1999;McCarron et al 2010) acquired experimentally through photolysis of caged IP 3 in a small region of the cell (Wang and Augustine 1995). waves in the EC and SMC obtained experimentally through uniform agonist stimulus applied throughout the cell.…”