Physiologically detectable bisphenol A impairs human sperm functions by reducing protein-tyrosine phosphorylation

Cholecystokinin (CCK), a peptide hormone and a neurotransmitter, was detected in mature sperm two decades ago. However, the exact role of CCK and the types of CCK receptors (now termed CCK1 and CCK2) in sperm have not been identified. Here, we find that CCK1 and CCK2 receptors are immunolocalized to the acrosomal region of mature sperm. The antagonist of CCK1 or CCK2 receptor strongly activated the soluble adenylyl cyclase/cAMP/protein kinase A signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation in dose- and time-dependent manners. But these actions of stimulation were abolished when sperm were incubated in the medium in the absence of HCO3−. Further investigation demonstrated that the inhibitor of CCK1 or CCK2 receptor could accelerate the uptake of HCO3−and significantly elevate the intracellular pH of sperm. Interestingly, the synthetic octapeptide of CCK (CCK8) showed the same action and mechanism as antagonists of CCK receptors. Moreover, CCK8 and the antagonist of CCK1 or CCK2 receptor were also able to accelerate human sperm capacitation-associated protein tyrosine phosphorylation by stimulating the influx of HCO3−. Thus, the present results suggest that CCK and its receptors may regulate sperm capacitation-associated protein tyrosine phosphorylation by modulating the uptake of HCO3−.

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Role of protein tyrosine phosphorylation in the thapsigargin-induced intracellular Ca2+ store depletion during human sperm acrosome reaction

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gag017 ◽

2003 ◽

Vol 9 (3) ◽

pp. 125-131 ◽

Cited By ~ 23

Author(s):

V. Dorval

Keyword(s):

Tyrosine Phosphorylation ◽

Acrosome Reaction ◽

Human Sperm ◽

Protein Tyrosine Phosphorylation ◽

Protein Tyrosine ◽

Store Depletion ◽

Sperm Acrosome Reaction ◽

Sperm Acrosome

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Capacitation-associated protein tyrosine phosphorylation and membrane fluidity changes are impaired in the spermatozoa of asthenozoospermic patients

Reproduction ◽

10.1530/rep.1.00584 ◽

2005 ◽

Vol 129 (6) ◽

pp. 697-705 ◽

Cited By ~ 32

Author(s):

Mariano G Buffone ◽

Juan C Calamera ◽

Sandra V Verstraeten ◽

Gustavo F Doncel

Keyword(s):

Membrane Fluidity ◽

Tyrosine Phosphorylation ◽

Plasma Membranes ◽

Phosphodiesterase Inhibitor ◽

Human Sperm ◽

Computer Assisted ◽

Protein Tyrosine Phosphorylation ◽

Membrane Composition ◽

Protein Tyrosine ◽

Camp Analog

Sperm protein tyrosine phosphorylation has been associated with capacitation, motility changes, zona binding, and fertilizing ability. We previously demonstrated that gradient-isolated human sperm subpopulations differ in their plasma membrane composition, their ability to phosphorylate proteins in tyrosine residues, and their capacity to undergo hyperactivation. In this study, we have characterized capacitation-associated changes in protein tyrosine phosphorylation and membrane fluidity in spermatozoa of asthenozoospermic and normozoospermic patients consulting for infertility. Semen samples were studied at baseline and after a capacitating incubation with or without the addition of a permeable cAMP analog and a phosphodiesterase inhibitor. Basic sperm and computer-assisted motion parameters, hyperactivation, protein tyrosine phosphorylation (immunofluorescence and Western blot), and membrane fluidity (fluorescent Laurdan probe) were the main study parameters. In comparison with normozoospermic and proven-fertile donor semen, asthenozoospermic samples showed lower motility, velocity, and amplitude of lateral head displacement, both originally and after a 6-h capacitating incubation. Unlike those in normal samples, asthenozoospermic spermatozoa were unable to increase protein tyrosine phosphorylation during capacitation. Such impairment, however, was overcome when they were incubated with a membrane-permeable cAMP analog and a phosphodiesterase inhibitor, indicating a possible membrane defect. Confirming this hypothesis, plasma membranes of asthenozoospermic sperm showed decreased fluidity (increased Laurdan polarization), even after a capacitating incubation. In conclusion, spermatozoa from functional asthenozoospermic samples may owe their poor motility, and their inability to properly capacitate and develop hyperactivation, to an impairment in the tyrosine phosphorylation of critical proteins caused by decreased membrane fluidity. These findings suggest a molecular pathogenetic mechanism for a common seminal pathology associated with male infertility.

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