Non‐selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP

Abstract

Throughout the body there are smooth muscle cells controlling a myriad of tubes and reservoirs. The cells show enormous diversity and complexity compounded by a plasticity that is critical in physiology and disease. Over the past quarter of a century we have seen that smooth muscle cells contain -as part of a gamut of ion-handling mechanisms -a family of cationic channels with significant permeability to calcium, potassium and sodium. Several of these channels are sensors of calcium store depletion, G-protein-coupled receptor activation, membrane stretch, intracellular Ca 2+ , pH, phospholipid signals and other factors. Progress in understanding the channels has, however, been hampered by a paucity of specific pharmacological agents and difficulty in identifying the underlying genes. In this review we summarize current knowledge of these smooth muscle cationic channels and evaluate the hypothesis that the underlying genes are homologues of Drosophila TRP (transient receptor potential). Direct evidence exists for roles of TRPC1, TRPC4/5, TRPC6, TRPV2, TRPP1 and TRPP2, and more are likely to be added soon. Some of these TRP proteins respond to a multiplicity of activation signals -promiscuity of gating that could enable a variety of context-dependent functions. We would seem to be witnessing the first phase of the molecular delineation of these cationic channels, something that should prove a leap forward for strategies aimed at developing new selective pharmacological agents and understanding the activation mechanisms and functions of these channels in physiological systems.

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

“…The closely related subgroup comprising TRPC3, TRPC6, and TRPC7 channels are directly activated by diacylglycerol through a PKC-independent mechanism (3,4). TRPC6 channels are highly expressed in a number of different tissues including vascular smooth muscle cells (5)(6)(7)(8). Despite their abundance, the exact physiological role of TRPC6 channels has not been elucidated.…”

“…TRPC6 channels are expressed predominantly in cells responding to hydrostatic pressure changes including vascular smooth muscle and glomerular podocytes and have been implicated in mediating pressure-induced responses (6,13). TRPC6 channels mediate receptor-induced depolarization in smooth muscle cells (7,9), and opening of the related TRPC1 channel has been shown to be activated by stretch (14).…”

“…Despite their abundance, the exact physiological role of TRPC6 channels has not been elucidated. Recently it has been suggested that TRPC6 channels are involved in hemodynamic regulation (6,9) and may play a role in generating myogenic tone in response to intravascular pressure in arteries (6,9). This is a key mechanism to control blood flow in arteries and arterioles (10,11) involving depolarization, activation of Ca 2ϩ entry, and the contraction of vascular smooth muscle cells (11).…”

“…TRPC6 channels mediate receptor-induced depolarization in smooth muscle cells (7,9), and opening of the related TRPC1 channel has been shown to be activated by stretch (14). In addition to being implicated in generating myogenic tone in arteries (6,9), elevated expression of TRPC6 channels has been linked to smooth muscle proliferation in patients with idiopathic pulmonary arterial hypertension (15). TRPC6 is also shown to be essential for proper function of podocytes that are exposed to hydrostatic pressure driving glomerular ultrafiltration in the kidney (13).…”

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

“…gated Ca 2ϩ permeable cation channels, important determinants of vascular function and disease (2,4,5,13). These channels can be constitutively active or activated by various physiological stimuli, including receptor agonists, Ca 2ϩ store depletion, and membrane stretch (2).…”