Expression of temperature-sensitive ion channel TRPM8 in sperm cells correlates with vertebrate evolution

Abstract

Transient Receptor Potential cation channel, subfamily Melastatin, member 8 (TRPM8) is involved in detection of cold temperature, different noxious compounds and in execution of thermo- as well as chemo-sensitive responses at cellular levels. Here we explored the molecular evolution of TRPM8 by analyzing sequences from various species. We elucidate that several regions of TRPM8 had different levels of selection pressure but the 4th–5th transmembrane regions remain highly conserved. Analysis of synteny suggests that since vertebrate origin, TRPM8 gene is linked with SPP2, a bone morphogen. TRPM8, especially the N-terminal region of it, seems to be highly variable in human population. We found 16,656 TRPM8 variants in 1092 human genomes with top variations being SNPs, insertions and deletions. A total of 692 missense mutations are also mapped to human TRPM8 protein of which 509 seem to be delateroiours in nature as supported by Polyphen V2, SIFT and Grantham deviation score. Using a highly specific antibody, we demonstrate that TRPM8 is expressed endogenously in the testis of rat and sperm cells of different vertebrates ranging from fish to higher mammals. We hypothesize that TRPM8 had emerged during vertebrate evolution (ca 450 MYA). We propose that expression of TRPM8 in sperm cell and its role in regulating sperm function are important factors that have guided its molecular evolution, and that these understandings may have medical importance.

Phylogenetic inference identifies two eumetazoan TRPM clades and an 8th family of TRP channel, TRP soromelastatin (TRPS)

“…S13 ). Although immunohistochemical evidence has previously suggested that TRPM8 is present in teleost fish (Majhi, et al 2015), we found no evidence of it in available sequences for ray-finned fish, cartilaginous fish, or agnathans ( Fig. 6 and Fig.…”

Comparison of Bioinformatics Prediction, Molecular Modeling, and Functional Analyses ofFOXC1Mutations in Patients with Axenfeld-Rieger Syndrome

“…The Align‐GVGD Web‐based server integrates the biophysical features of amino acids and protein multiple sequence alignments to predict whether missense variants in genes of interest lead to deleterious or neutral effects. This program is an extension of the original Grantham difference to multiple sequence alignments and true simultaneous multiple comparisons [Majhi et al., ]. For Align‐GVGD program, a value of C > 0 was considered deleterious; otherwise a variant was considered to be neutral.…”

Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data

“…[8][9][10] In agreement with these reports, recent studies have indeed confirmed that different domains and motifs of TRP channels had undergone differential selection pressure throughout vertebrate evolution. 3,5,11 This leads to changes in the sequence of TRP channels, especially in certain key regions affecting its structure -function relationship, which is either beneficial (thus selected) or may become deleterious (thus not selected) during molecular evolution.…”

“…For example, Zebra fish lost TRPM8 during evolution, most likely to increase their reproductive fitness in the cold region of Himalayas where that species have evolved under resource limited conditions. 3 In fact, different species seem to have utilized TRPM8 to respond to different temperatures. This is supported by that fact that African clawed frog Xenopus laevis has a very distinct thermal response property compared to its mammalian and avian counterparts.…”

“…However, crucial inference can be drawn from the 1092 and now from 2504 human genome data which provides suitable platform for comparative studies. 3,[12][13] A systemic analysis of 2504 genome data suggests that there is a high variability in all TRPV family members including the thermo-sensitive channels namely in TRPV1-TRPV4 (Table 1). To investigate the substitutions occurring in human population (which is~1% of total population), the use of SIFT, PolyPhen and GD scores proved to be very helpful, especially in categorizing various probably deleterious mutations (Fig.…”