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.