GPR62 constitutively activates cAMP signaling but is dispensable for male fertility in mice

Abstract

G-protein-coupled receptors (GPCRs) participate in diverse physiological functions and are promising targets for drug discovery. However, there are still over 140 orphan GPCRs whose functions remain to be elucidated.Gpr62is one of the orphan GPCRs that is expressed in the rat and human brain. In this study, we found thatGpr62is also expressed in male germ cells in mice, and its expression increases along with sperm differentiation. GPR62 lacks the BBXXB and DRY motifs, which are conserved across many GPCRs, and it was able to induce cAMP signaling in the absence of a ligand. These structural and functional features are conserved among mammals, and the mutant analysis of GPR62 has revealed that lacking of these motifs is involved in the constitutive activity. We also found that GPR62 can homooligomerize, but it is not sufficient for its constitutive activity. We further investigated its physiological function by usingGpr62knockout (Gpr62−/−) mice.Gpr62−/−mice were born normally and did not show any abnormality in growth and behavior. In addition, both male and femaleGp62−/−mice were fertile, and the differentiation and motility of spermatozoa were normal. We also found thatGpr61, the gene most similar toGpr62in the GPCR family shows a constitutive activity and an expression pattern similar to those ofGpr62. Our results suggest that GPR62 constitutively activates the cAMP pathway in male germ cells but is dispensable for male fertility, which is probably due to its functional redundancy with GPR61.