P540TRPC channel lipid specificity and mechanisms of lipid regulation

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Abstract

TRPC channels are the Canonical (C) subset of the Transient Receptor Potential (TRP) proteins, which are widely expressed in mammalian cells. In humans there are 6 TRPCs (TRPC1, 3-7) which assemble together, or with other TRPs, in groups of 4 to form single channels. The channels are thought to be primarily involved in determining calcium and sodium entry and have wide-ranging functions that include regulation of cell proliferation, motility, and contraction. In the cardiovascular system the channels have been suggested to have importance in remodelling, such as that of cardiac hypertrophy after aortic restriction. An apparently special player is the TRPC1 channel subunit, which is up-regulated in vascular injury and promotes hyperplasia of smooth muscle cells in human saphenous vein (Kumar et al 2006 Circ Res 98, 557-). TRPC1 forms heteromultimeric assemblies with other TRP channel subunits that include TRPC5 (Xu et al 2006 Circ Res 98, 1381-). The channels are modulated by a multiplicity of factors, putatively existing as integrators at the plasma membrane.There are sensitivities of the TRPC channels to lipids that include diacylglycerols, phosphatidylinositol bisphosphate, lysophospholipids, arachidonic acid and its metabolites, sphingosine-1-phosphate, cholesterol and some steroidal derivatives, and other lipid factors such as gangliosides (Beech 2011 Acta Physiol published on-line). Of particular relevance to the cardiovascular system is the stimulation of TRPC1-TRPC5 heteromultimeric channels by specific oxidized phospholipids, acting through Gi/o-protein signalling without calcium-release (AL-Shawaf et al 2010, ATVB 30, 1453-). Promiscuous as well as selective lipid sensing have been detected. However, there appear to be particularly close working relationships with lipids of the phospholipase C and A2 enzyme systems, enabling integration with receptor signalling and membrane stretch. There are differences in the properties of each TRPC channel that are complicated by TRPC heteromultimerisation. The lipids modulate activity of the channels or insertion in the plasma membrane. Lipid microenvironments and intermediate sensing proteins have been described that include caveolae, G protein signalling, SESTD1, and podocin. The data suggest that lipid-sensing is an important aspect of TRPC channel biology, enabling integration with other signalling systems. Financial support is kindly provided by the Wellcome Trust, Medical Research Council, and British Heart Foundation.

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