The function and structural influence of selective relaxed constraint at functional intracellular loop3 of 5-HT1A serotonin-1 receptor family

Serotonin (5-HT) and its receptors have been involved in critical signal transduction mechanism and deregulation implicated in mood-related disorders. 5-HT activities are mediated through a family of transmembrane spanning serotonin receptors. Both within the family and species, 5-HT receptor protein sequence diversity and 7-transmembrane structural homogeneity have long been intriguing. In this study, we have analyzed the codon site constraint in 5-HT1 subclass receptors from 13 orthologous mammalian mRNA coding sequence. Further, the study was extended to computationally investigate the impact of non-synonymous sites with respect to function and structural significance through sequence homology algorithm and molecular dynamics simulation (MDS). Codon sites with significant posterior probability were observed in 5-HT1A, 5‐HT1B and 5-HT1D receptor indicating variations in site constraint within the 5‐HT1 sub-class genes. In 5-HT1A receptor, seven sites were detected at the functional intracellular loop3 (ICL3) with higher substitution rate through Codeml program. Sequence homology algorithm identifies that these sites were functionally tolerant within the mammals representing a selectively relaxed constraint at this domain. On the other hand, the root mean square deviation (rmsd) values from MDS suggest differences in structural conformation of ICL3 models among the species. Specifically, the human ICL3 model fluctuation was comparatively more stable than other species. Hence, we argue that these sites may have varying influence in G-proteins coupling and activation of effectors systems through downstream interacting accessory proteins of cell among the species. However, further experimental studies are required to elucidate the precise role and the seeming difference of these sites in 5-HT receptors between species.

► 5-HT1 receptor genes from 13 mammals were examined. ► Codon sites with significant posterior probability were observed in 5-HT1A, 5‐HT1B and 5-HT1D receptors. ► Human 5-HT1A ICL3 peptide model was found to be comparatively more stable within the orthologous mammalian species.