Transient Receptor Potential Channels in the Vasculature

Abstract

The mammalian genome encodes 28 distinct members of the transient receptor potential (TRP) superfamily of cation channels, which exhibit varying degrees of selectivity for different ionic species. Multiple TRP channels are present in all cells and are involved in diverse aspects of cellular function, including sensory perception and signal transduction. Notably, TRP channels are involved in regulating vascular function and pathophysiology, the focus of this review. TRP channels in vascular smooth muscle cells participate in regulating contractility and proliferation, whereas endothelial TRP channel activity is an important contributor to endothelium-dependent vasodilation, vascular wall permeability, and angiogenesis. TRP channels are also present in perivascular sensory neurons and astrocytic endfeet proximal to cerebral arterioles, where they participate in the regulation of vascular tone. Almost all of these functions are mediated by changes in global intracellular Ca(2+) levels or subcellular Ca(2+) signaling events. In addition to directly mediating Ca(2+) entry, TRP channels influence intracellular Ca(2+) dynamics through membrane depolarization associated with the influx of cations or through receptor- or store-operated mechanisms. Dysregulation of TRP channels is associated with vascular-related pathologies, including hypertension, neointimal injury, ischemia-reperfusion injury, pulmonary edema, and neurogenic inflammation. In this review, we briefly consider general aspects of TRP channel biology and provide an in-depth discussion of the functions of TRP channels in vascular smooth muscle cells, endothelial cells, and perivascular cells under normal and pathophysiological conditions.

Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries

“…TRPC6 and TRPC3 channels are permeant to Na ϩ and Ca 2ϩ , IP 3 R1 is a Ca 2ϩ -selective channel, and TRPM4 is a Na ϩ -selective channel (12,26). Data supporting signaling from TRPC6 to ANO1 include Hyp9 activation of Cl Ϫ currents and blockade of Hyp9 activation of Cl Ϫ currents by both T16Ainh-A01 and selective ANO1 knockdown in myocytes.…”

“…Ca 2ϩ is a principal intracellular activator of ANO1 channels, but the source(s) of Ca 2ϩ that activate ANO1 and ion channels that generate these intracellular Ca 2ϩ signals is unclear (4). Intracellular Ca 2ϩ signals can arise from the opening of plasma membrane Ca 2ϩ -permeant channels, including voltage-dependent Ca 2ϩ and transient receptor potential (TRP) channels and intracellular Ca 2ϩ release from sarcoplasmic reticulum (SR) ryanodine-sensitive Ca 2ϩ release channels and inositol trisphosphate receptors (IP 3 Rs) (12,14,17,26). In cerebral artery myocytes, ANO1 channels are activated by local Ca 2ϩ influx through yet unidentified plasma membrane nonselective cation channels (5).…”

“…, and Cl Ϫ , as well as nonselective cation channels (4,12,14,19). An understanding of the signaling processes that control the activity of these ion channels provides a better understanding of mechanisms that regulate arterial contractility.…”

“…Selective ANO1 knockdown attenuated intravascular pressure-induced cerebral artery depolarization and vasoconstriction (5). Cell-specific knockout of ANO1 reduced Cl Ca currents in aortic and cerebral arteriole myocytes, agonist-induced vasoconstriction in retinal and skeletal muscle arterioles, and systemic blood pressure and attenuated hypertension in mice (15) (12,14,17,26). In cerebral artery myocytes, ANO1 channels are activated by local Ca 2ϩ influx through yet unidentified plasma membrane nonselective cation channels (5).…”

“…In cerebral artery myocytes, ANO1 channels are activated by local Ca 2ϩ influx through yet unidentified plasma membrane nonselective cation channels (5). Arterial myocytes are proposed to express nonselective cation channels, including multiple members of the TRP family (12). The goal of this study was to identify plasma membrane nonselective cation channels that control ANO1 currents in cerebral artery myocytes.…”