A New Insight into the Function of TRPV2 in Circulatory Organs

The TRPV subfamily has had increasing attention since some channels in this group have been shown to be sensitive to a broad range of environmental stimuli, including heat, osmosensitivity, and mechanical stress. In addition, TRPV proteins are widely expressed in a range of cell types in lower and higher organisms. Although some TRPVs were originally found in the sensory system, ubiquitous expression in the whole body suggests that they play important roles in both sensory and nonsensory transduction functions. All mammalian homologues of TRPVs are calcium-permeable channels, with TRPV1–4 characterized as moderately calcium-selective cationic channels (Nilius, Voets et al. 2005; O'Neil and Brown 2003; Benham, Davis et al. 2002). This calcium permeability is physiologically important because Ca has an obligatory role in regulating diverse cellular functions (e.g., fertilization, muscle contraction, exocytosis, and so on). There is increasing evidence that TRPV1–4 are sensitive to physical stimuli such as osmolarity, stretching, and shear stress (Liedtke and Kim 2005; O'Neil and Heller 2005). Whereas TRPV4 appears to be crucial for some relevant forms of cellular mechanosensitivity, the activation of TRPVs by mechanostress has not been fully elucidated for all channels of this group (O'Neil and Heller 2005). Cellular responses to stretch or shear stimuli by blood flow are one of the key elements in muscle tone regulation (Figure 28.1A). In cell-attached and inside-out patch-recording modes, membrane stretch applied through the recording pipette activates nonselective cationic channels in vascular smooth muscles (Kirber et al. 1988; Davis et al. 1992; Ohya et al. 1998; see review: Beech et al. 2004). The unitary conductances range from 8 to 64 pS for monovalent cations, and a cationic channel blocker, Gd, is effective to block the channel. In whole-cell recordings, application of longitudinal cell stretch or cell swelling by pressure on the patch pipette or hypotonic bath solution also evokes Ca-permeable cationic currents in vascular myocytes (Davis et al. 1992). Additionally, in cardiac atrial and ventricular myocytes, nonselective cationic channels are activated by cell swelling as well as membrane stretch (Clemo and Baumgarten 1997; Zhang et al. 2000; Kamkin et al. 2003). Similar nonselective cationic channels sensitive to mechanical stimuli including shear stress are also identified in vascular endothelial cells (Lansman et al. 1987; Oike et al. 1994; see review: Nilius and Droogmans 2001). Although extensive studies to identify a molecular candidate of these mechanosensitive channels have been performed, information is still limited (Kanzaki, Nagasawa et al. 1999; Gillespie and Walker 2001). Nevertheless, the mechanosensitive nature of the channels seems to be conserved in higher organisms for some TRP channels, and it is likely that TRPC1, TRPC6, TRPV2, TRPM4, TRPA1, TRPP1, and possibly TRPV4 are potential candidates for the mechanosensitive channels in various native organs (Maroto et al. 2005; Welsh et al. 2002; Muraki et al. 2003; Iwata et al. 2003; Earley, Waldron et al. 2004; Corey et al. 2004; Nauli et al. 2003; Liedtke 2005). In this section, we focus on expression, function, and mechanosensitivity of TRPV2 (a member of the vanilloid receptor TRP subfamily) in circulatory organs such as vascular smooth muscles, cardiac muscles, and the endothelium. Heat activation and trafficking mechanisms of TRPV2 and expression of TRPV2 in neuronal organs will be discussed in another section (Caterina et al. 1999; Kanzaki, Zhang et al. 1999; Boels et al. 2001; Barnhill et al. 2004; Benham, Gunthorpe et al. 2003).