PHOSPHORYLATION BY CA+2/CALMODULIN-DEPENDENT KINASE II REGULATES BINDING OF CAPSAICIN TO VR1

초록

VR1, a capsaicin receptor, is now known to play a major role in mediating inflammatory thermal nociception. Although the physiological role or biophysical properties of VR1 are known, its activation mechanisms by ligands are poorly understood. Here, we show that VR1 requires phosphorylation by Ca2+-calmodulin-dependent kinase II (CaMKII) for its activation by capsaicin. In contrast, dephosphorylation by calcineurin, leads to desensitization of the receptor. Point mutation of VR1 at two putative consensus sites for CaMKII fails to elicit capsaicin-sensitive currents with concomitant reduction in phosphorylation of VR1 in vivo. The mutant also lost the high-affinity binding of 3H-resiniferatoxin, a potent capsaicin-receptor agonist. We conclude that the dynamic balance between phosphorylation and dephosphorylation of the channel by CaMKII and calcineurin controls the activation/desensitization state by regulating the binding property. Furthermore, since sensitization by protein kinase A and C converges on these sites, phosphorylation stress in the cell appears to control a wide range of excitability in response to various adverse stimuli.