Molecular Diversity of Receptor Operated Channels in Vascular Smooth Muscle

Abstract

See related article, pages 1520–1527 The mammalian transient receptor potential (TRP) superfamily of cation channels includes at least 29 individual genes divided into 6 subfamilies based on sequence homology.1 Like many ion channel proteins, TRP subunit polypeptide sequences encode 6 transmembrane domains, with a putative pore-forming loop between the fifth and sixth membrane spanning region. Functional ion-permeable channels are formed from the assembly of 4 TRP polypeptide subunits as a tetrameric complex. Typically, biophysical properties and regulation of TRP channels have been elucidated by studying cultured cells overexpressing a single cloned TRP subunit gene. Under these conditions, the overexpressed protein is the primary TRP subunit present, and channels are predominately formed from 4 identical TRP subunits, ie, “homomeric” TRP channels. Although this experimental approach has yielded abundant valuable information, it does not accurately reflect the in vivo state because native cells generally express a number of individual TRP channel genes, allowing the formation of ion channels composed of 2 or more TRP subunits, ie, “heteromultimeric” TRP channels. The existence of heteromultimeric TRP channels was first demonstrated when coexpression of the Drosophila TRP and TRPL genes in cultured cells gave rise to whole-cell currents that were distinct from those of cells expressing TRP or TRPL homomeric channels, and physical interaction between these 2 proteins in Drosophila photoreceptor cells was demonstrated by coimmunoprecipitation.2 Heteromultimeric TRP channels in native mammalian cells were first reported when subunits TRPC1 and TRPC5 from the canonical TRP (TRPC) subfamily were shown to colocalize in the rat hippocampus and, using coimmunoprecipitation, were found to form a molecular complex in brain microsomes.3 A whole-cell current was recorded from HEK cells coexpressing TRPC1 and TRPC5 that was distinct from recordings obtained from cells expressing either TRPC1 or TRPC5 alone, providing further evidence that TRPC1 and TRPC5 …