Conclusions
(1) Male infertility rates have continuously increased in recent years, and few effective treatments with known targets and defined mechanisms exist. Recently, the identification of mutations in specific GPCR superfamily members related to male infertility and the increased understanding of the detailed molecular mechanisms involving these GPCRs in the regulation of sperm maturation and homeostasis of the microenvironments of the epididymis and efferent ductules have provided new clues on the potential development of therapies to treat male infertility, given that these receptors account for almost 1/3 of current clinical drug targets.
(2) In addition to ADGRG2 and AGTR2, GPCR superfamily members such as LGR4, GPER, and adenosine receptors are known to play important roles in the regulation of postnatal epididymal development, the formation of the blood-epididymal barrier, the maintenance of osmotic pressure in a perfusion solution and the contractility of the epididymis (Table 1). The repertoire of the physiological roles of these GPCRs and other uncharacterized GPCRs, as well as further detailed studies of these receptor connecting to male infertility development, provide entirely novel therapeutic opportunities for the treatment of male infertility.
(3) Currently, various small-molecule compounds, peptide ligands and endogenous ligands have been found or developed to target AGTR2, LGR4, GPER and adenosine receptors (Table 3). It is worth noting that several such compounds or ligands have been approved by the FDA for the treatment of diseases other than male infertility. Therefore, there is great interest in testing these ligands and compounds in male infertility animal models to examine their therapeutic potential. It is also worth noting that endogenous or high-affinity ligands involved in the regulation of ADGRG2 have not been identified. Such tools are greatly needed to understand the function of ADGRG2 in male fertility and evaluate the potential role of ADGRG2 as a therapeutic target in male infertility.
(4) Only a small number of the signaling pathways downstream of GPCRs have been characterized in detail in the efferent ductules and epididymis, and these pathways have shown unique signaling properties, although they sometimes share signal-transducing effectors (Figure 1). For example, both ADGRG2 and GPER have been shown to couple to Gs in the epididymis; however, they exhibit distinct subcellular microdomain biases in their signaling. ADGRG2 forms a signal transduction complex with β-arrestin-1, Gq and CFTR on the apical membrane, whereas GPER forms a complex with Gs at the endoplasmic reticulum, nuclear envelope and plasma membrane (Figure 1). Therefore, even when sharing effectors, the location bias of each GPCR may determine its detailed specific functions in the epididymis and efferent ductules. This possibility raises the question of whether activation of an alternative GPCR in the epididymis or efferent ductules will be able to rescue the dysfunction of a particular GPCR, such as in cases of infertility caused by the ADGRG2 mutations.
(5) Collectively, the complex signaling of GPCR members in the epididymis and the specific physiological roles of these GPCRs that contribute to male fertility are worthy of further detailed investigation. In addition, the prospect of using their ligands highlights new opportunities for potential therapies development for male infertility.