Functional Significance of Transient Receptor Potential Channels in Vascular Function

Abstract

Membrane ion channels are critical mediators of vascular endothelial and smooth muscle cell function and regulate diverse properties of blood vessels such as arterial tone, angiogenesis, and permeabilty. Although physiological roles for many ion channels and transporters are well established, the functional significance of transient receptor potential (TRP) channels in the vasculature is just beginning to be elucidated. This chapter summarizes the current understanding of these cation channels in vascular function. For a more in-depth overview of TRP channel biology, the reader is directed to several excellent general reviews covering this topic [1–4].As shown in Table 26.1, the mammalian TRP superfamily of cation channels contains at least 22 genes grouped into three major subfamilies based on sequence homology: TRPV (vanilloid), TRPC (canonical), and TRPM (melastatin). Three additional subfamilies (the “distant TRPs”), TRPP (polycystin), TRPML (mucolipin), and TRPA have been proposed, bringing the total number of TRP-related proteins to around 30. Although these channels were initially described in sensory neurons, it is now thought that most cell types express several TRP genes. TRP proteins are expressed as six transmembrane-domain polypeptide subunits, and it is believed that four subunits assemble in the plasma membrane to form functional channels. All TRP channels are cation permeable, and most are not selective for monovalent versus divalent ions. Exceptions include TRPV5 and TRPV6, which display significant specificity for Ca2+ ions, and TRPM4 and TRPM5, which are highly selective for monovalent cations and impermeant to Ca2+ TRP channels are activated by a variety of stimuli, including changes in pressure, temperature, osmolarity, and intracellular Ca2+ Fatty acids and receptor-dependent vasoconstrictor agonists also activate vascular TRP channels. This diversity of ionic conductivity and activating mechanisms is consistent with the possibility that members of the TRP superfamily may contribute to regulation of a variety of physiological systems.Elucidation of functional roles for TRP channels in vascular cells may be hindered by the complex molecular biology of the superfamily. Biophysical properties of TRP channels have been investigated in patch-clamp experiments employing cultured cells expressing cloned TRP subunit genes. Under these conditions, most functional channels assemble from four identical TRP subunits. However, when multiple TRP subunits are coexpressed, assembly of tetramers composed of two or more TRP subunit proteins can form heteromeric channels [5,6] with novel properties [7,8]. Because most cells express multiple TRP subunits, it is likely that heteromeric channels exist in vivo. Furthermore, splice variants of TRP mRNAs in smooth muscle have been reported [9], potentially increasing the number of individual subunits available for coassembly. Because TRP molecular variety could result in an assortment of channels with a wide array of functional properties in native cells, unraveling the physiological consequences of TRP channel diversity presents a major challenge. In the following paragraphs, evidence for the presence and possible functional roles of TRP channels in vascular smooth muscle and endothelial cells are discussed.