Abstract
TRPV5 and TRPV6 are inwardly rectifying calcium selective channels, considered as gatekeepers of epithelial calcium transport and key elements for calcium homeostasis. Intracellular calcium exert a negative control over the activity of these channels. In mammals, TRPV6 channels show a characteristic fast calcium-dependent inactivation phase, that is absent in TRPV5 channels at physiological conditions. It has been evidenced that the intracellular loop located between the transmembrane segments (TM) S2-S3 and residues downstream the TM S6 are involved in the mechanism of fast inactivation, however the molecular mechanism driving fast inactivation is not known. In the present study we establish a structural-functional correlation of this process. By means of electrophysiological recordings we identified a set of conserved residues at the Helix-Loop-Helix (HLH) domain that modulates the inactivation phenotype. Molecular dynamics simulations suggest that the inactivation phenotype can be explained by specific conformational changes induced by calcium coordination to a structural triad formed by the HLH domain, the intracellular connector between TM S2-S3, and the TRP helix.
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