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Review
. 2011 May;13(3):395-405.
doi: 10.1038/aja.2010.69.

Ion channels, phosphorylation and mammalian sperm capacitation

Pablo E Visconti  1 , Dario Krapf, José Luis de la Vega-Beltrán, Juan José Acevedo, Alberto Darszon
Affiliations
Review

Ion channels, phosphorylation and mammalian sperm capacitation

Pablo E Visconti et al. Asian J Androl. 2011 May.

Abstract

Sexually reproducing animals require an orchestrated communication between spermatozoa and the egg to generate a new individual. Capacitation, a maturational complex phenomenon that occurs in the female reproductive tract, renders spermatozoa capable of binding and fusing with the oocyte, and it is a requirement for mammalian fertilization. Capacitation encompasses plasma membrane reorganization, ion permeability regulation, cholesterol loss and changes in the phosphorylation state of many proteins. Novel tools to study sperm ion channels, image intracellular ionic changes and proteins with better spatial and temporal resolution, are unraveling how modifications in sperm ion transport and phosphorylation states lead to capacitation. Recent evidence indicates that two parallel pathways regulate phosphorylation events leading to capacitation, one of them requiring activation of protein kinase A and the second one involving inactivation of ser/thr phosphatases. This review examines the involvement of ion transporters and phosphorylation signaling processes needed for spermatozoa to achieve capacitation. Understanding the molecular mechanisms leading to fertilization is central for societies to deal with rising male infertility rates, to develop safe male gamete-based contraceptives and to preserve biodiversity through better assisted fertilization strategies.

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Figures

Figure 1
Figure 1
Ion permeability model. This figure illustrates a schematic representation of the roles and interrelationships between the ion transporters suspected to participate in capacitation. Capacitation and hyperactivation take place during sperm transit through the female tract and have parallel but also intercrossing pathways. Cholesterol removal from the sperm plasma membrane by albumin in the female tract modifies several membrane properties. Albumin can also directly stimulate CatSper channels, increasing [Ca2+]i. The HCO3− increase experienced by sperm upon entering the female reproductive tract elevates intracellular HCO3− possibly through a NBC which would cause a hyperpolarization and stimulation of SACY, producing cAMP. In addition to triggering the phosphorylation cascades (see Figure 2), cAMP may activate the sNHE which together with the proton channel (HV), possibly stimulated by Zn2+ removal in the female reproductive tract, would raise pHi and activate CatSper and Slo3 channels. cAMP would also activate CFTR and participate in closing ENaCs which together with K+ channels hyperpolarize sperm. The [Ca2+]i increase may influence glycolysis and the axoneme activity promoting hyperactivated motility. Several Ca2+ mobilizing pumps (PMCA4 and SPCA1) and channels (IP3R, RyR and TRPs) may also participate during Ca2+ signaling. Not all sperm species undergo an Em hyperpolarization associated to capacitation like mouse; the channels and transporters that may contribute to this hyperpolarization are indicated. CFTR, cystic fibrosis transmembrane regulator; Em, membrane potential; IP3R, IP3 receptor; NBC, Na+/HCO3− cotransporter; NKCC, Na+/K+/Cl− cotransporter; PKA, protein kinase A; RyR, ryanodine receptor; SACY, soluble adenylyl cyclase; sNHE, sperm Na+/H+ exchanger; TRP, transient receptor potential.
Figure 2
Figure 2
Model of the regulation of phosphorylation pathways during mammalian sperm capacitation. The overall pathway is modulated by cholesterol removal of sperm plasma membrane. formula image Influx of HCO3− and Ca2+ stimulates an SACY. formula image Increasing intracellular cAMP concentrations. formula image High cAMP levels activate PKA. This activation can be blocked in vitro by addition of the inhibitors H-89, Rp-cAMPs and the peptide PKI. formula image In vivo, phosphorylation of PKA substrates is subjected to regulation by a ser/thr phosphatase, likely PP2A. This phosphatase is in turn downregulated by a member of the Src kinase family by still unknown mechanisms. Activation of Src kinase family members can be blocked by in vitro addition of the inhibitors SU6656 or SKI-606 (Bosutinib). The onset of PKA substrates phosphorylation is followed by activation of unidentified tyrosine kinases formula image and the promotion of tyrosine phosphorylation of sperm proteins formula image (e.g., AKAP4, AKAP3, VCP and CABYR). formula image Intracellular Ca2+ increase might affect the axoneme directly, through selective regulation of dyneins. In addition, Ca2+ upregulates CaMKIV, leading to hyperactivation. PKA, protein kinase A; PKC, protein kinase C; PKI, protein kinase inhibitor; SACY, soluble adenylyl cyclase; VCP, valosin-containing protein.
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