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Insights into Activation Mechanisms of Store-Operated TRPC1 Channels in Vascular Smooth Muscle.

Baudel, MASM-A; Shi, J; Large, WA; Albert, AP (2020) Insights into Activation Mechanisms of Store-Operated TRPC1 Channels in Vascular Smooth Muscle. Cells, 9 (1). ISSN 2073-4409
SGUL Authors: Albert, Anthony Paul

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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.

Item Type: Article
Additional Information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
Keywords: Gq, MARCKS, Orai1, PIP2, PKC, PLC, STIM1, TRPC1, store-operated channels, vascular smooth muscle
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Cells
ISSN: 2073-4409
Language: eng
10 January 2020Published
5 January 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Project IDFunderFunder ID
BB/J007226/1Biotechnology and Biological Sciences Research Council
BB/M018350/1Biotechnology and Biological Sciences Research Council
PubMed ID: 31936855
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