Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors, consisting of five subtypes (M1 to M5). These receptors play different roles in autocrine and neuronal systems and are important in the physiology and pathophysiology of various organs. Activation of mAChRs may affect cell proliferation, differentiation, growth and other functions in the male reproductive tract. This review focuses on the identification and function of mAChR subtypes in the male reproductive tract with emphasis on the signaling transduction pathways activated by the agonist-mAChR complex in rat Sertoli cells. The unique localization of mAChR subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate found in various species have suggested a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction. In Sertoli cells, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) through βγ-subunits of G proteins that promote Src-mediated metalloprotease-dependent cleavage and the release of EGFR ligands from the cell surface, to be followed by the binding of these ligands to EGFR and activation of extracellular signal-regulated kinases (ERK)1/2. Furthermore, an increase on ERK1/2 phosphorylation via phospholipase Cβ (PLCβ) and intracellular Ca++ mobilization dependent mechanisms is also involved, but no involvement of protein kinase C (PKC) is observed. The transactivation of EGFR by the agonist-mAChR complex is also involved in Sertoli cell proliferation. Since receptors are targets for pharmacological manipulation of physiological processes, these studies may be important for the development of selective therapeutic agents and new approaches in fertility/infertility and/or male contraception.
Keywords: Muscarinic receptors, male reproductive tract, Sertoli cells, EGFR transactivation, ERK1/2 activation, male fertility, male infertility
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