The novel high-frequency variant of TRPV3 p.A628T in East Asians showing faster sensitization in response to chemical agonists

초록

TRPV3, a member of the thermosensitive Ca2+-permeable TRPV channel subfamily expressed in skin and sensory nerves, is also activated by chemical agonists such as 2-aminoethyl diphenylborinate (2-APB). Repetitive stimuli induce sensitization of TRPV3 activation, characterized by the cumulative increase in current amplitude and linearization of current-voltage relation (I/V curve). Through genomic analysis of various populations, we found non-rare TRPV3 mutation (p.A628T) in East Asian people with an allele frequency of 0.249 while 0.007 in Caucasian. Slope conductance of unitary channel was not different between WT and p.A628T. Whole-cell patch clamp study of wildtype TRPV3 (WT) and p.A628T overexpressed in HEK293T cells showed similar sensitization by the repetitive increase in temperature from 23 to 37 degrees C, while slightly higher sensitization to 43 degrees C in p.A628T. In contrast, the repetitive application of 2-APB (10 mu M) or carvacrol (100 mu M) induced faster sensitization in p.A628T than WT. However, 1 mu M farnesyl pyrophosphate, an intrinsic lipid metabolite agonist, induced similar level of slow activations in WT and p.A628T. In Fura-2 microspectrofluorimetry, the 2-APB pulses induced a faster increase of [Ca2+](c) in p.A628T than WT. In terms of ionic selectivity of channels, WT and p.A628T showed similar Ca2+ permeability (P-Ca/P-Na) calculated from the reversal potential of I/V curves. Taken together, p.A628T shows faster sensitization to chemical agonists that are reflected as higher [Ca2+](c) signaling. Based on the intriguing pharmacological sensitivity, the physiological implications of p.A628T in the East Asian population require further investigation.

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