Mechanistic insights into sperm cyclic adenosine monophosphate (cAMP) signaling: Relevance for male infertility and contraceptive development

Abstract

Cyclic adenosine monophosphate (cAMP) signaling pathways play a pivotal role in mammalian sperm physiology, particularly in regulating capacitation, a complex series of biochemical events that enable sperm to acquire fertilization competence. During the early stages of capacitation, an increase in cAMP concentration, driven by the activation of soluble adenylyl cyclase (sAC), activates different downstream effectors, including the protein kinase A (PKA). Activation of these pathways modulates the acquisition of hyperactivated motility in the flagellum and the occurrence of acrosomal exocytosis in the head. This review summarizes recent advances made in the last decade on this topic, with special emphasis on methodologies for analyzing cAMP dynamics and the regulation of cAMP production and its effects during capacitation. Special attention is given to the canonical mechanisms controlling sAC activity through bicarbonate and calcium, as well as emerging evidence for non-canonical modes of regulation. The complex and sometimes controversial interplay between the sAC/cAMP/PKA pathway and the calcium channel CatSper is discussed in depth, along with current knowledge in downstream cAMP effectors in sperm. Finally, the review highlights how modulation of the cAMP pathways may be exploited to either enhance sperm motility and function as a strategy to treat male infertility or, conversely, to inhibit sperm signaling as a potential non-hormonal contraceptive approach.