A genetic variant of the sperm-specific SLO3 K⁺ channel has altered pH and Ca²⁺ sensitivities

To fertilize an oocyte, sperm must first undergo capacitation in which the sperm plasma membrane becomes hyperpolarized via activation of potassium (K⁺) channels and resultant K⁺ efflux. Sperm-specific SLO3 K⁺ channels are responsible for these membrane potential changes critical for fertilization in mouse sperm, and they are only sensitive to pHi. However, in human sperm, the major K⁺ conductance is both Ca²⁺-and pHi-sensitive. It has been debated whether Ca²⁺-sensitive SLO1 channels substitute for human SLO3 (hSLO3) in human sperm or whether human SLO3 channels have acquired Ca²⁺ sensitivity. Here we show that hSLO3 is rapidly evolving and reveal a natural structural variant with enhanced apparent Ca²⁺ and pH sensitivities. This variant allele (C382R) alters an amino acid side chain at a principal interface between the intramembranegated pore and the cytoplasmic gating ring of the channel. Because the gating ring contains sensors to intracellular factors such as pH and Ca²⁺, the effectiveness of transduction between the gating ring and the pore domain appears to be enhanced. Our results suggest that sperm-specific genes can evolve rapidly and that natural genetic variation may have led to a SLO3 variant that differs from wild type in both pH and intracellular Ca²⁺ sensitivities. Whether this physiological variation confers differences in fertility among males remains to be established.