ZD7288 inhibits low-threshold Ca(2+) channel activity and regulates sperm function

In this study, ZD7288, a blocker of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, has been found to inhibit the mouse sperm acrosome reaction (AR). HCN channels have not yet been either recorded or implicated in mouse sperm AR, but low-threshold (T-type) Ca(2+) channels hav...

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Published in:Biochemical and biophysical research communications 2003-11, Vol.311 (1), p.187-192
Main Authors: Felix, Ricardo, Sandoval, Alejandro, Sánchez, Daniel, Gómora, Juan Carlos, De la Vega-Beltrán, José L, Treviño, Claudia L, Darszon, Alberto
Format: Article
Language:English
Subjects:
Acrosome Reaction - drug effects
Animals
Calcium Channels, T-Type - drug effects
Calcium Channels, T-Type - physiology
Cells, Cultured
Dose-Response Relationship, Drug
Humans
Ion Channel Gating - drug effects
Ion Channel Gating - physiology
Kidney - drug effects
Kidney - physiology
Male
Membrane Potentials - drug effects
Mice
Pyrimidines - pharmacology
Spermatozoa - drug effects
Spermatozoa - physiology
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Summary:In this study, ZD7288, a blocker of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, has been found to inhibit the mouse sperm acrosome reaction (AR). HCN channels have not yet been either recorded or implicated in mouse sperm AR, but low-threshold (T-type) Ca(2+) channels have. Interestingly, ZD7288 blocked native T-type Ca(2+) currents in mouse spermatogenic cells with an IC(50) of about 100 microM. This blockade was more effective at voltages producing low levels of inactivation, suggesting a differential affinity of ZD7288 for different channel conformations. Furthermore, ZD7288 inhibited all cloned T-type but not high-threshold N-type channels heterologously expressed in HEK-293 cells. Our results further support the role of T-type Ca(2+) channels in the mouse sperm AR.
ISSN:0006-291X
DOI:10.1016/j.bbrc.2003.09.197