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Review
. 2012 Nov;14(6):816-21.
doi: 10.1038/aja.2012.81. Epub 2012 Sep 24.

Mechanism of sperm capacitation and the acrosome reaction: role of protein kinases

Debby Ickowicz  1 , Maya Finkelstein, Haim Breitbart
Affiliations
Review

Mechanism of sperm capacitation and the acrosome reaction: role of protein kinases

Debby Ickowicz et al. Asian J Androl. 2012 Nov.

Abstract

Mammalian sperm must undergo a series of biochemical and physiological modifications, collectively called capacitation, in the female reproductive tract prior to the acrosome reaction (AR). The mechanisms of these modifications are not well characterized though protein kinases were shown to be involved in the regulation of intracellular Ca(2+) during both capacitation and the AR. In the present review, we summarize some of the signaling events that are involved in capacitation. During the capacitation process, phosphatidyl-inositol-3-kinase (PI3K) is phosphorylated/activated via a protein kinase A (PKA)-dependent cascade, and downregulated by protein kinase C α (PKCα). PKCα is active at the beginning of capacitation, resulting in PI3K inactivation. During capacitation, PKCα as well as PP1γ2 is degraded by a PKA-dependent mechanism, allowing the activation of PI3K. The activation of PKA during capacitation depends mainly on cyclic adenosine monophosphate (cAMP) produced by the bicarbonate-dependent soluble adenylyl cyclase. This activation of PKA leads to an increase in actin polymerization, an essential process for the development of hyperactivated motility, which is necessary for successful fertilization. Actin polymerization is mediated by PIP(2) in two ways: first, PIP(2) acts as a cofactor for phospholipase D (PLD) activation, and second, as a molecule that binds and inhibits actin-severing proteins such as gelsolin. Tyrosine phosphorylation of gelsolin during capacitation by Src family kinase (SFK) is also important for its inactivation. Prior to the AR, gelsolin is released from PIP(2) and undergoes dephosphorylation/activation, resulting in fast F-actin depolymerization, leading to the AR.

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Figures

Figure 1
Figure 1
A model describing the involvement of various kinases in sperm capacitation and the AR. The model is composed of three steps: (a) Beginning of capacitation. (b) Ongoing capacitation. (c) The AR. (a) Beginning of capacitation. Activation of NBC and CatSper results in fast increase in intracellular HCO3− and Ca2+ resulting in SACY/PKA activation. Later on efflux of cholesterol from the sperm plasma membrane enhances further bicarbonate permeability into the cell resulting in further activation of SACY, cAMP production and PKA activation. PKA activation leads to Src-mediated gelsolin phosphorylation maintaing PIP2-bound gelsolin in an inactive state and thereby stabilizing the polymerized actin. At the beginning of capacitation process, PKCα is in its active state which leads to PP1γ2 phosphorylation/activation. PP1γ2 causes PI3K dephosphorylation/inhibition. At this stage, the level of PIP2 increases, resulting in PLD activation which produces PA leading to actin polymerization. (b) Ongoing capacitation. PKA mediates proteasome dependent PKCα and PP1γ2 degradation, leading to PI3K phosphorylation/activation. During capacitation, Ca2+ concentration is elevated, EGFR is partially activated resulting in PI3K activation. At this stage, gelsolin still bound to PIP2 in an inactive state and thereby depolymerization of F actin is prevented. (c) The AR. Sperm binding to the egg ZP stimulates relatively high elevation of intracellular Ca2+ and EGFR is activated, leading to PLCγ and PI3K activation. PI3K phosphorylation can also occur by PKA activation. PLCγ hydrolyzes PIP2 resulting in DAG and IP3 production. DAG activates PKC and IP3 activates Ca2+ efflux from the acrosome. The decrease in PIP2 levels results in the release of gelsolin to the cytosol following by its dephosphrylation/activation by tyrosine phosphatases leading to F-actin depolimerization and the occurrence of the AR. AR, acrosome reaction; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; NBC, Na+/HCO3− cotransporter; PA, phosphatidic acid; PI3K, phosphatidyl-inositol-3-kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PLD, phospholipase D; SACY, soluble adenylyl cyclase; ZP, zona pellucida.
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