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.