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

Abstract

Important for calcium homeostasis, TRPV5 and TRPV6 are calcium-selective channels belonging to the transient receptor potential (TRP) gene family. In this study, we investigated the evolutionary history of these channels to add an evolutionary context to the already available physiological information. Phylogenetic analyses revealed that paralogs found in mammals, sauropsids, amphibians, and chondrichthyans, are the product of independent duplication events in the ancestor of each group. Within amniotes, we identified a traceable signature of three amino acids located at the amino-terminal intracellular region (HLH domain). The signature correlates well with both the duplication events and the phenotype of fast inactivation observed in mammalian TRPV6 channels. Electrophysiological recordings and mutagenesis suggest that calcium-induced fast inactivation represents an evolutionary innovation that emerged independently after gene duplication.

Parallel evolution of placental calcium transfer in the lizard Mabuya and eutherian mammals

“…This expression pattern is similar to what occurs in the uterine and extraembryonic membranes in pigs, mice, humans and bovines, in which the highest level of TRPV6 expression usually occurs in the last trimester of pregnancy (Lee et al, 2009;Sprekeler et al, 2012), indicating it plays an active role in calcium transport to the fetus (Lee et al, 2009). The origin of trpv5 and trpv6 within tetrapods corresponded to independent duplication events, in amphibians, sauropsids and mammals (Flores-Aldama et al, 2020). The ancestor species of each lineage had a single copy of a trpv5/6 gene, and independent lineage-specific duplication events resulted in a repertoire of trpv5 and trpv6 genes in each lineage.…”

“…The epithelial calcium channels TRPV5 and TRPV6 are highly selective ion channels implicated in Ca 2+ (re)absorption in all vertebrates; they play vital physiological roles in calcium homeostasis from fish gills to metanephric kidneys (Flores-Aldama et al, 2020). The two calcium channels exhibit similarities in many ways, as they share a high level of amino acid sequence identity, comparable functional properties, and similar mechanisms of regulation.…”

“…The two calcium channels exhibit similarities in many ways, as they share a high level of amino acid sequence identity, comparable functional properties, and similar mechanisms of regulation. Yet, their physiological contributions toward maintaining a systemic calcium balance are distinct (Flores-Aldama et al, 2020;Peng et al, 1999).…”