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The four sperm-specific CatSper ion channel proteins are required for hyperactivated motility and male fertility, and for Ca 2+  entry evoked by alkaline depolarization. In the absence of external Ca 2+ , Na +  carries current through CatSper channels in voltage-clamped sperm. Here we show that CatSper channel activity can be monitored optically with the [Na + ] i -reporting probe SBFI in populations of intact sperm. Removal of external Ca 2+  increases SBFI signals in wild-type but not CatSper2-null sperm. The rate of the indicated rise of [Na + ] i  is greater for sperm alkalinized with NH 4 Cl than for sperm acidified with propionic acid, reflecting the alkaline-promoted signature property of CatSper currents. In contrast, the [Na + ] i  rise is slowed by candidate CatSper blocker HC-056456 (IC 50  ∼3 µM). HC-056456 similarly slows the rise of [Ca 2+ ] i  that is evoked by alkaline depolarization and reported by fura-2. HC-056456 also selectively and reversibly decreased CatSper currents recorded from patch-clamped sperm. HC-056456 does not prevent activation of motility by HCO 3   −  but does prevent the development of hyperactivated motility by capacitating incubations, thus producing a phenocopy of the CatSper-null sperm. When applied to hyperactivated sperm, HC-056456 causes a rapid, reversible loss of flagellar waveform asymmetry, similar to the loss that occurs when Ca 2+  entry through the CatSper channel is terminated by removal of external Ca 2+ . Thus, open CatSper channels and entry of external Ca 2+  through them sustains hyperactivated motility. These results indicate that pharmacological targeting of the CatSper channel may impose a selective late-stage block to fertility, and that high-throughput screening with an optical reporter of CatSper channel activity may identify additional selective blockers with potential for male-directed contraception.

Pharmacological Targeting of Native CatSper Channels Reveals a Required Role in Maintenance of Sperm Hyperactivation