Everything you ever wanted to know about PKA regulation and its involvement in mammalian sperm capacitation

The 3′, 5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA) is a tetrameric holoenzyme comprising a set of two regulatory subunits (PKA-R) and two catalytic (PKA-C) subunits. The PKA-R subunits act as sensors of cAMP and allow PKA-C activity. One of the first signaling events observed during mammalian sperm capacitation is PKA activation. Thus, understanding how PKA activity is restricted in space and time is crucial to decipher the critical steps of sperm capacitation. It is widely accepted that PKA specificity depends on several levels of regulation. Anchoring proteins play a pivotal role in achieving proper localization signaling, subcellular targeting and cAMP microdomains. These multi-factorial regulation steps are necessary for a precise spatio-temporal activation of PKA. Here we discuss recent understanding of regulatory mechanisms of PKA in mammalian sperm, such as post-translational modifications, in the context of its role as the master orchestrator of molecular events conducive to capacitation. •PKA activity is restricted in space and time during critical steps of sperm capacitation.•Anchoring proteins play a pivotal role in achieving proper localization signaling, subcellular targeting and cAMP microdomains.•Multi-factorial regulation steps are necessary for a precise spatio-temporal activation of PKA.