Potentiation of TRPV3 channel function by unsaturated fatty acids.

Transient receptor potential (TRP) channels have emerged as cellular sensors of physical and chemical changes inside and outside cells (Clapham, 2003). Six TRP channels have been shown to be involved in temperature sensing in sensory neurons and skin. TRPA1 and TRPM8 are involved in detecting cool to cold temperatures while TRPV1, V2, V3, V4 are responsible for sensing warm to noxious heat. In addition to thermosensation, these channels also respond to inflammatory mediators, implicating their involvement in inflammatory pain and tissue injury-induced thermal hyperalgesia. For example, TRPV1 is activated by bradykinin, nerve growth factor, and ATP through signaling pathways mediated by activation of their respective receptors (Cesare et al., 1999; Chuang et al., 2001; Tominaga et al., 2001) and by tissue acidosis as a consequence of inflammation and malignant tumor growth (Reeh and Kress, 2001). Hypotonicity-induced activation of TRPV4 in primary afferent nociceptive nerve fibers is enhanced by prostaglandin E2 (Alessandri-Haber et al., 2003). TRPA1 is activated by bradykinin through activation of phospholipase C (Bandell et al., 2004). In the inflamed tissues, arachidonic acid (AA) is either released from the infiltrating lymphocytes or produced within the sensory fibers or skin cells following the activation of receptors by other inflammatory mediators. While the lipoxygenase products of AA directly activate TRPV1 (Hwang et al., 2000; Shin et al., 2002), the epoxygenase products are responsible for the stimulatory effect of AA on TRPV4 (Watanabe et al., 2003). TRPV3 may be involved in the sensation of warm to noxious heat. The reported temperature threshold values for TRPV3 ranged from 31 to 39°C (Peier et al., 2002; Smith et al., 2002; Xu et al., 2002) and the channel was continuously activated up to 50°C (Xu et al., 2002). Expression of TRPV3 protein has been shown in mouse skin keratinocytes (Chung et al., 2003, 2004a) and in sensory neurons of human dorsal root ganglia (Smith et al., 2002). Knockout of TRPV3 gene from mice led to impaired responses to innocuous and noxious heat, which are believed to be due to a defect in thermasensation in the skin cells (Moqrich et al., 2005). Recently, we, and others, showed that TRPV3 channels are activated by 2-aminoethoxydiphenyl borate (2APB) (Hu et al., 2004; Chung et al., 2004b). With the use of 2APB, TRPV3-mediated heat-sensitive currents were detected in primary keratinocytes isolated from TRPV4−/− mice (Chung et al., 2004b). Because of the sequence homology and functional similarities between TRPV3 and other heat-sensitive channels, it has been speculated that TRPV3 also plays a role in thermal hypersensitivity induced by tissue injury and inflammation (Smith et al., 2002). Here we show that TRPV3 channel function is greatly enhanced by AA via a mechanism that does not require the oxidation of the fatty acid and the effect can be mimicked by other unsaturated fatty acids, including non-metabolizable analogues of AA. The potentiation by fatty acids is not mediated through protein kinase C (PKC) even though activation of PKC also causes an increase of TRPV3 activity. Parts of the results have appeared in an abstract form (Hu et al., 2005).