Cdc42 activity is necessary for the interplay between cAMP/PKA pathway and CatSper function

XU X; ORTA G; GILIO N; JABLOÑSKI M; KRAPF D; LUQUE GM; GERVASI MG; STIVAL C; BALESTRINI PA; VISCONTI PE; BUFFONE MG; ROMAROWSKI A; DE LA VEGA-BELTRAN JL; DALOTTO-MORENO T; KRAPF D; DARSZON A

Congreso; Gordon Research Conference: Fertilization and Activation of Development.; 2019

Sperm acquire the ability to fertilize in the female genital tract in a process called capacitation. From a molecular point of view, bicarbonate stimulation of the soluble adenylyl cyclase (sAC) leads to the activation of the cAMP/PKA pathway. During capacitation, sperm undergo changes in the motility pattern called hyperactivation, which depends on Ca2+ transport by the sperm-specific Ca2+ channel CatSper. CatSper is essential for fertilization and therefore, it is subjected to a complex regulation that is not fully understood. Here we report that, similar to CatSper, Cdc42 distribution in the principal piece is confined to four linear domains and this localization is disrupted in CatSper-null sperm. Cdc42 inhibition impaired CatSper activity and other Ca2+-associated events resulting in a severe compromise of the sperm fertilizing potential. We also demonstrate that Cdc42 is essential for CatSper function by modulating cAMP production by sAC, providing a new regulatory mechanism for the upregulation of CatSper by the cAMP/PKA-dependent pathway. These results reveal a broad mechanistic insight into the regulation of Ca2+ in mammalian sperm, a matter of critical importance in male infertility as well as in contraception.