Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels

Fundamental for calcium homeostasis in vertebrates, TRPV5 and TRPV6 are calcium-selective ion channels belonging to the Transient Receptor Potential (TRP) gene family. Detailed phylogenetic analysis suggests that duplications from which TRPV5 and TRPV6 originated occurred independently in the ancestors of mammals, sauropsids, amphibians, and chondrichthyans. Coincident with the conquest of land and the physiological changes needed to maintain calcium homeostasis, our expression analyses suggest a change in the expression pattern from gills to kidney. Within amniotes, we identified a traceable sequence signature of three amino acids at the amino-terminal intracellular region that correlates well with both of the duplication events and the phenotype of fast inactivation observed in TRPV6 channels. Electrophysiological recordings and mutagenesis suggest that calcium-induced fast inactivation is an evolutionary innovation that emerged independently from each duplication event. Simulations of molecular dynamics suggest that calcium-induced channel rearrangements are important modulatory regions of TRP channels.