Fertilization requires calcium signalling at several levels. First, sperm cell motility and chemotaxis are regulated by calcium currents induced by the sperm cells' interaction with the outer layers of the egg. Second, penetration of the outer layers of the egg by the sperm cell requires the exocytosis of enzymes from the sperm cells, a process called the acrosome reaction, which is also calcium-dependent. Last, after fertilization, calcium transients in the egg are required for its activation.

David Clapham and his colleagues now identify a new calcium channel, CaSper, which is specifically expressed in the tail region of sperm cells (see picture; left, phase-contrast image; right, immunofluorescence staining for CaSper) and is required for their motility and for male fertility (Nature 413, 603–609, 2001). Inactivation of the corresponding gene leads to male sterility in mice that are otherwise healthy. Sperm cells from these mice fail an in vitro fertilization assay and their motility is markedly reduced. However, sperm-cell adherence to the egg is normal, and mutant sperm cells can fertilize eggs provided that their extracellular matrix is removed enzymatically. Because of the specificity of its expression pattern, CaSper is an ideal target for contraceptive drugs for both men and women.

So how does CaSper work? It bears structural homology to voltage-dependent potassium channels and sequence homology to voltage-dependent calcium channels. Clapham and colleagues wished to study the electrophysiological properties of the CaSper channel, but patch clamp studies are still unsuccessful in the tail region of sperm cells because of technical limitations. The authors therefore turned to spermatocytes instead, but they saw no defects in voltage-gated calcium currents in CaSper-deficient cells. Experiments in which CaSper was ectopically expressed in Xenopus oocytes and in mammalian cells also proved inconclusive because no currents could be measured through CaSper by patch clamping. But CaSper-deficient sperm cells show no cyclic-AMP-induced calcium influx, suggesting that CaSper is either gated by cyclic nucleotides or activated by the depolarization caused by native cyclic-nucleotide-gated channels. The authors speculate that CaSper-dependent channels could in turn activate calcium-dependent adenylyl cyclases and cAMP production in a positive feedback loop.