Abstract
ABSTRACTStore depletion has been shown to induce Ca2+ entry by Na+/Ca+ exchange (NCX) 1 reversal in proliferative vascular smooth muscle cells (VSMCs). The study objective was to investigate the role of transient receptor potential canonical (TRPC) channels in store depletion and NCX1 reversal in proliferative VSMCs. In cultured VSMCs, expressing TRPC1, TRPC4, and TRPC6, the removal of extracellular Na+ was followed by a significant increase of cytosolic Ca2+ concentration that was inhibited by KBR, a selective NCX1 inhibitor. TRPC1 knockdown significantly suppressed store-operated, channel-mediated Ca2+ entry, but TRPC4 knockdown and TRPC6 knockdown had no effect. Separate knockdown of TRPC1, TRPC4, or TRPC6 did not have a significant effect on thapsigargin-initiated Na+ increase in the peripheral regions with KBR treatment, but knockdown of both TRPC4 and TRPC6 did. Stromal interaction molecule (STIM)1 knockdown significantly reduced TRPC4 and TRPC6 binding. The results demonstrated that TRPC4–TRPC6 heteromultimerization linked Ca2+ store depletion and STIM1 accumulation with NCX reversal in proliferative VSMCs.
Highlights
The regulation of intracellular calcium concentration ([Ca2+]i is an important control of vascular smooth muscle cell (VSMC) proliferation [1]
Western blot assays showed that TRPC1, TRPC4, and TRPC6 were expressed in cultured vascular smooth muscle cells (VSMCs) (Fig. 1A)
TRPC4 protein expression was higher in primary cultures of proliferative aortic VSMCs and cultured A7r5 cells than in VSMCs freshly isolated from the aortic media
Summary
The regulation of intracellular calcium concentration ([Ca2+]i is an important control of vascular smooth muscle cell (VSMC) proliferation [1]. Known regulators of [Ca2+] in VSMCs include Na+/ Ca2+ exchange (NCX), voltage-operated Ca2+ channels, and receptor-operated Ca2+ channels (ROC) in the plasma membrane (PM), which include second messenger-gated channels, ionotropic receptors, and store-operated calcium channels (SOCC) [2,3]. Ca2+ entry mediated by SOCC and NCX1 reversal-mediated Ca2+ entry are both known to influence VSMC proliferation and NCX1 is involved in the migration and proliferation of pulmonary artery smooth muscle, gastrointestinal myofibroblast, and fibroblast cell lines [5,6,7]. When Ca2+ in the ER store is depleted, STIM1 relocates to the PM and combines with calcium release-activated calcium modulator 1 (ORAI1) which mediates Ca2+ entry. NCX1 is a PM ion transporter expressed in the PM of VSMCs [9] that usually acts in forward mode to transport Ca2+
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