Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension

Abstract

Increased vascular tone in essential hypertension involves a sustained rise in total peripheral resistance. A model has been proposed in which the combination of membrane depolarization and higher L-type Ca channel activity generates augmented Ca influx into vascular smooth muscle cells (VSMCs), contraction and vasoconstriction. The search for culprit ion channels responsible for membrane depolarization has provided several candidates, including members of the canonical transient receptor potential (TRPC) family. TRPC3 and TRPC6 are diacylglycerol-activated, non-selective cationic channels contributing to stretch- or agonist-induced depolarization. Conflicting information exists regarding changes in TRPC3/TRPC6 functional expression in hypertension. However, although TRPC3-TRPC6 channels can heteromultimerize, the possibility that differences in their association pattern may change their functional contribution to vascular tone is largely unexplored. We probe this hypothesis using a model of essential hypertension (BPH mice; blood pressure high) and its normotensive control (BPN mice; blood pressure normal). First, non-selective cationic currents through homo- and heterotetramers recorded from transfected Chinese hamster ovary cells indicated that TRPC currents were sensitive to the selective antagonist Pyr10 only when TRPC6 was present, whereas intracellular anti-TRPC3 antibody selectively blocked TRPC3-mediated currents. In mesenteric VSMCs, basal and agonist-induced currents were more sensitive to Pyr3 and Pyr10 in BPN cells. Consistently, myography studies showed a larger Pyr3/10-induced vasodilatation in BPN mesenteric arteries. mRNA and protein expression data supported changes in TRPC3 and TRPC6 proportions and assembly, with a higher TRPC3 channel contribution in BPH VSMCs that could favour cell depolarization. These differences in functional and pharmacological properties of TRPC3 and TRPC6 channels, depending on their assembly, could represent novel therapeutical opportunities.

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

“…Measurement of oxidants and antioxidants in the aorta showed that this may be attributable to elevated SOD activity and reduced catalase activity leading to greater production of hydrogen peroxide and decreased catalase-mediated conversion of hydrogen peroxide to water (Uddin et al, 2003b). Different expression of canonical transient receptor potential (TRPC) 3 channels and of hetero-multimeric TRPC channels may also contribute to differences in vascular tone in the BPH/2 mice (Alvarez-Miguel et al, 2017).…”

Modulation of Transient Receptor Potential Channels 3 and 6 Regulates Osteoclast Function with Impact on Trabecular Bone Loss

“…Osteoclast function might rely on an equilibrium between TRPC3 and TRPC6, leading to bone loss in mice lacking TRPC6. Recent studies showed discrepancies regarding expression and functional contribution of these channels [23,24], which may be related to the fact that the contribution of TRPC3 and TRPC6 channels depends on their association as homo-or heterotetrameric complexes and differences in their association pattern may change their function [25].…”

TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

“…For instance, Bae et al [72] showed that the TRPC6 expression was enhanced in the mesenteric artery of DOCA-salt hypertensive rats, suggesting that aldosterone evoked TRPC6 upregulation, receptor-operated Ca 2+ entry (ROCE) and consequently hypertension development. [62][63][64]. They are involved in agonist-induced Ca 2+ increase and vasomotion in arteries from SHRs [64].…”