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

AbstractSperm acquire the ability to fertilize in a process called capacitation and undergo hyperactivation, a change in the motility pattern, which depends on Ca2+ transport by CatSper channels. CatSper is essential for fertilization and 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 CatSper1-null sperm. Cdc42 inhibition impaired CatSper activity and other Ca2+-dependent downstream 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 stimulation 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.

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Decoding the regulatory mechanism of glucose and insulin induced phosphatidylinositol 3,4,5-trisphosphate dynamics in β-cells

Molecular BioSystems ◽

10.1039/c7mb00227k ◽

2017 ◽

Vol 13 (8) ◽

pp. 1512-1523

Author(s):

Tagari Samanta ◽

Peeyush Sharma ◽

Dwijendra Kukri ◽

Sandip Kar

Keyword(s):

Mathematical Modeling ◽

Regulatory Mechanism ◽

Β Cells ◽

Mechanistic Insight ◽

Synergistic Activation ◽

Insight Into ◽

Modeling Study

Mathematical modeling study provides mechanistic insight into the glucose and insulin mediated synergistic activation of PIP3in MIN6 β-cells.

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Mechanisms of action of angiotensin II on mammalian sperm function

Reproduction ◽

10.1530/rep.1.00457 ◽

2005 ◽

Vol 129 (2) ◽

pp. 211-218 ◽

Cited By ~ 9

Author(s):

Samra Mededovic ◽

Lynn R Fraser

Keyword(s):

Angiotensin Ii ◽

Pertussis Toxin ◽

Fluorescence Analysis ◽

Camp Production ◽

Receptor Coupling ◽

Mammalian Sperm ◽

Significant Acceleration ◽

Intracellular Ca ◽

Inhibitory G Protein ◽

Stimulation Of

Angiotensin II (AII) stimulates capacitation and fertilizing ability in mammalian spermatozoa, with the binding of AII to its receptors resulting in stimulation of cAMP production in both uncapacitated and capacitated cells. This study investigated possible mechanisms whereby AII affects cAMP availability. The first question was whether extracellular Ca2+is required for responses in mouse spermatozoa and, using chlortetracycline fluorescence analysis, it was clear that cells responded to AII only when the medium contained CaCl2, with both 90 μM and 1.80 mM supporting a significant acceleration of capacitation. Consistent with those results, AII significantly stimulated cAMP production in both CaCl2-containing media tested, the response being greater in that containing 1.80 mM. Several different agents that might affect the signalling pathway stimulated by AII were then evaluated in uncapacitated suspensions. Chlortetracycline analysis revealed that pertussis toxin abolished responses to AII, suggesting the involvement of an inhibitory Gα subunit; dideoxyadenosine, a specific membrane-associated adenylyl cyclase (mAC) P-site inhibitor, also blocked responses, suggesting involvement of an mAC. cAMP determinations con-firmed that both reagents also abolished AII’s stimulation of cAMP. In contrast, nifedipine, a Ca2+channel blocker, did not inhibit AII’s effects on spermatozoa. Finally, in capacitated suspensions, both pertussis toxin and dideoxyadenosine were again shown to block AII’s stimulation of cAMP. These results suggest that responses to AII involve an inhibitory G protein and an mAC, but it is likely that AII–receptor coupling does not stimulate directly mAC but rather does so in an indirect manner, perhaps by altering the intracellular Ca2+concentration.

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