Journal of Andrology
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Published-Ahead-of-Print April 1, 2006, DOI:10.2164/jandrol.05152

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SAMMA induces premature human acrosomal loss by Ca2+ signaling dysregulation

Robert A. Anderson , Kenneth A. Feathergill , Donald P. Waller , and Lourens J.D. Zaneveld

SAMMA is licensed for development as a contraceptive microbicide. Understanding mechanisms of its biological activity is prerequisite to designing more active second generation products. This study examined Ca2+ involvement in SAMMA-induced premature acrosomal loss (SAL) in noncapacitated human spermatozoa. SAMMA causes acrosomal loss (AL) in a dose-dependent manner (ED50 = 0.25 g/mL). SAL requires extracellular Ca2+ (ED50 = 85 M). SAL is inhibited by verapamil (non-specific voltage-dependent Ca2+ channel blocker; IC50 = 0.4 M), diphenylhydantoin and NiCl2 (T-type (Cav3.x) channel blockers; IC50 210 M and 75 M, respectively). Verapamil blockade of L-type (Cav1.x)channels is use-dependent; activated channels are more sensitive to inhibition. However, verapamil inhibition of SAL does not increase after repeated SAMMA stimulation. SAL is unaffected by 10 M nifedipine (selective L-type channel blocker). This contrasts to 40% inhibition (p < 0.001) of AL induced by 1 M thapsigargin (Ca2+-ATPase inhibitor; releases intracellular Ca2+ stores, promotes capacitative Ca2+ entry). SAL is unaffected by 1 M BAPTA-AM (intracellular Ca2+ chelator), and 50 M 2-APB (blocks InsP3 receptors and store-operated channels). This contrasts with thapsigargin-induced AL, inhibited nearly 65% by BAPTA-AM (p < 0.005) and 91% by 2-APB (p < 0.001). The results suggest that SAL is mediated by Ca2+ entry through channels pharmacologically similar to the T-type (Cav3.2) class. This process appears distinct from that due to physiological stimuli such as progesterone or zona pellucida-derived proteins. SAMMA's contraceptive activity may be due to induction of premature AL through dysregulation of Ca2+ signaling.






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