TRPV4: A Multifunctional Nonselective Cation Channel with Complex Regulation

Mammalian TRP channels form a large family with around thirty members. From sequence similarity, TRPs can be divided into three major TRP subfamilies: the lassical or anonical subfamily (TRPC), the elastatin-related subfamily (TRPM), and the anilloid-receptor–related subfamily (TRPV) [1]. In addition, there are a number of more distantly related subfamilies: TRPA (nkyrin), TRPP (olycystin), and TRPML (ucolipidin) [1–3]. TRPV1, the first member of the TRPV family and the sensory neuron receptor for vanilloid ligands like capsaicin, which is also responsive to noxious heat (>42°C), was found by expression cloning [4], as were the more distantly related epithelial Ca channels TRPV5 [5] and TRPV6 [6]. The other members, TRPV2 [7], TRPV4 (see below), and later TRPV3 [8–10], were found by homology screens. TRPV4 was found by screening expressed sequence tag databases for sequences with similarity to TRPV1, TRPV2, and the TRPV isoform OSM-9. Lacking a consensus on nomenclature at the time, TRPV4 was given a variety of names—OTRPC4 (OSM-9-like TRP channel 4) [11], VROAC (vanilloid receptor–related osmotically activated channel) [12], TRP12 [13] and VRL-2 (vanilloid receptor–like channel 2) [14]—by the different groups who cloned the channel. TRPV4 has 871 amino acids, and structural features of the channel are intracellular N- and C-termini, six membrane spanning segments (S1–S6), a reentrant pore-forming loop between S5 and S6, and at least three ankyrin domains in the cytosolic N-terminus (see, e.g., Figure 9.2). Even though TRPV4 shows sequence similarity to other members of the TRPV family, particularly to TRPV1–3, a coexpression study has indicated that TRPV4 preferentially forms homomers [15], and, as yet, there is no evidence for heteromultimeric combinations with other TRPVs.