Function and therapeutic potential of G protein-coupled receptors in epididymis

Abstract

Infertility rates for both females and males have increased continuously in recent years. Currently, effective treatments for male infertility with defined mechanisms or targets are still lacking. G protein-coupled receptors (GPCRs) are the largest class of drug targets, but their functions and the implications for the therapeutic development for male infertility largely remain elusive. Nevertheless, recent studies have shown that several members of the GPCR superfamily play crucial roles in the maintenance of ion-water homeostasis of the epididymis, development of the efferent ductules, formation of the blood-epididymal barrier and maturation of sperm. Knowledge of the functions, genetic variations and working mechanisms of such GPCRs, along with the drugs and ligands relevant to their specific functions, provide future directions and a great arsenal for new developments in the treatment of male infertility.

Keywords: ADGRG2; AT2 receptor; G protein-coupled receptor (GPCR); LGR4; epididymis; male infertility.

FIGURE 1

Diagram showing GPCR signalling and functions in the epididymis and efferent ductules. Above: The efferent ductules are a series of tubules that connect the rete testis to the epididymis. The epithelia of the efferent ductules are mainly composed of two cell types, ciliated cells and non‐ciliated cells. The epididymis is composed of one highly convoluted tubule. The epididymis is segmented morphologically and functionally into following distinct regions: the initial segment (not existing in human epididymis), the caput, the corpus, and the cauda. Each part consists of several cell types, including principal cells, narrow cells, clear cells, and basal cells. Inset: GPER activates cAMP‐CFTR‐chloride transportation to maintain the osmotic pressure of the perfusion solution. ADGRG2 is located exclusively on the apical membrane in non‐ciliated cells. ADGRG2/β‐arrestin1/G_q/CFTR forms a supercomplex that maintains pH and chloride anion homeostasis. AT₂ receptors are specifically detected in basal cells and are essential for the proton‐secretion function of the epididymal lumen through activation of the NO‐cGMP pathway. Different members of the adenosine receptor family have opposite effects on the contractility of the epididymis. LGR4 activates G_s to increase intracellular cAMP levels, which promote ERα expression

FIGURE 2

GPCR mutations associated with disease. The approximate positions of different mutations are indicated in the structures of ADGRG2 (A), AT₂ receptor (B), and LGR4 (C).. Abbreviations: GAIN domain: GPCR Autoproteolysis‐INducing domain; GPS, G protein‐coupled receptor proteolytic site; LRR, leucine‐rich repeats