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Calcium-dependent decrease in the single-channel conductance of TRPV1

Pflugers Archiv European Journal of Physiology, ISSN: 0031-6768, Vol: 462, Issue: 5, Page: 681-691
2011
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Article Description

TRPV1 is a Ca permeable cation channel gated by multiple stimuli including noxious heat, capsaicin, protons, and extracellular cations. In this paper, we show that Ca causes a concentration and voltage-dependent decrease in the capsaicin-gated TRPV1 single-channel conductance. This Ca -dependent effect on conductance was strongest at membrane potentials between -60 and +20 mV, but was diminished at more hyperpolarised potentials. Using simultaneous recordings of membrane current and fura-2 fluorescence to measure the fractional Ca current of whole-cell currents evoked through wild-type and mutant TRPV1, we investigated a possible link between the mechanisms underlying Ca permeation and the Ca -dependent effect on conductance. Surprisingly, we found no evidence of a structural correlation, and observed that the substitution of amino acids known to regulate Ca permeability had little effect on the ability for Ca to decrease TRPV1 conductance. However, we did observe that the Ca -dependent effect on conductance was not diminished by negative hyperpolarisation for a mutant receptor with severely impaired Ca permeability, TRPV1-D646N/E648Q/E651Q. This would be consistent with the idea that Ca reduces conductance by interacting with an intra-pore binding site, and that negative hyperpolarization reduces occupancy of this site by speeding the exit of Ca into the cell. Taken together, our data show that in addition to directly and indirectly regulating channel gating, Ca also directly reduces the conductance of TRPV1. Surprisingly, the mechanism underlying this Ca -dependent effect on conductance is largely independent of mechanisms governing Ca permeability. © 2011 Springer-Verlag.

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