Abstract
In vascular smooth muscle cells (VMSCs), the stimulation of store-operated channels (SOCs) mediate Ca2+ influx pathways which regulate important cellular functions including contraction, proliferation, migration, and growth that are associated with the development of vascular diseases. It is therefore important that we understand the biophysical, molecular composition, activation pathways, and physiological significance of SOCs in VSMCs as these maybe future therapeutic targets for conditions such as hypertension and atherosclerosis. Archetypal SOCs called calcium release-activated channels (CRACs) are composed of Orai1 proteins and are stimulated by the endo/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1) following store depletion. In contrast, this review focuses on proposals that canonical transient receptor potential (TRPC) channels composed of a heteromeric TRPC1/C5 molecular template, with TRPC1 conferring activation by store depletion, mediate SOCs in native contractile VSMCs. In particular, it summarizes our recent findings which describe a novel activation pathway of these TRPC1-based SOCs, in which protein kinase C (PKC)-dependent TRPC1 phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP2) are obligatory for channel opening. This PKC- and PIP2-mediated gating mechanism is regulated by the PIP2-binding protein myristoylated alanine-rich C kinase (MARCKS) and is coupled to store depletion by TRPC1-STIM1 interactions which induce Gq/PLCβ1 activity. Interestingly, the biophysical properties and activation mechanisms of TRPC1-based SOCs in native contractile VSMCs are unlikely to involve Orai1.
Highlights
In vascular smooth muscle cells (VSMCs), neurotransmitters and hormones such as noradrenaline, adrenaline, angiotensin II (Ang II), and endothelin 1 (ET-1) produce an increase in cytosolic Ca2+concentration (Ca2+ i )
TRPC1 was essential for store-operated interactions between Gq, PLCβ1, and stromal interaction molecule 1 (STIM1). These findings provide strong evidence that STIM1 is an essential molecule in activation of TRPC1-based store-operated channels (SOCs), and importantly it indicates that store-operated STIM1-TRPC1 interactions form the structural basis for stimulation of the Gq/PLCβ1 pathway required for protein kinase C (PKC)-dependent TRPC1 phosphorylation and channel opening by PIP2
TRPC1 subunits to form a receptor for Gq G-protein subunits which induces PLCβ1 activity, production of DAG, and PKC activity
Summary
In vascular smooth muscle cells (VSMCs), neurotransmitters and hormones such as noradrenaline, adrenaline, angiotensin II (Ang II), and endothelin 1 (ET-1) produce an increase in cytosolic Ca2+. There is substantial evidence that Ca2+ -permeable non-selective cation channels classified as receptor-operated (ROCs) and store-operated (SOCs) are expressed in VSMCs [1,2]. ROCs are defined as ion channels activated by receptor stimulation independently of IP3 -mediated depletion of SR Ca2+ stores, whereas SOCs are activated by pathways coupled to depletion of SR Ca2+. It is proposed that SOCs may be activated by Gq-protein-coupled receptor stimulation independently of store depletion, SOCs may function as ROCs [8] Together, these findings make it difficult to study ROCs and SOCs independently of each other using macroscopic measurements such as whole-cell patch clamp and Ca2+ signal recordings but possible using single channel recordings [9,10,11]. In the majority of these studies SOCs were activated by SR Ca2+ ATPase inhibitors or Ca2+ chelators to prevent complications from activation of ROCs, in the final section we discuss the potential physiological significance of this store-operated activation pathway in vasoconstrictor-induced TRPC1-based SOCs
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