Abstract
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 pH i However, in human sperm, the major K+ conductance is both Ca2+- and pH i -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 intramembrane-gated 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.
Highlights
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
We found that the percentage of non-synonymous singlenucleotide polymorphism (SNP) in the human SLO3 gene was much higher than in the SLO1 gene (66 versus 43%, respectively)
MgCl2,10 mM Hepes, 10 mM MES, pH 7.2; and statistics are shown in Table 1 at the indicated pHi for WT and C382R variant. t tests comparing human SLO3 (hSLO3)-WT and hSLO3-C382R were performed at each pH; p values at pH 6, 7, 8, and 9 are 0.024, Ͻ0.001, Ͻ0.001, and 0.027, respectively
Summary
We previously demonstrated that mouse and bovine SLO3 protein sequences are 62.1% identical. We found that the percentage of non-synonymous SNPs (which change the amino acid sequence) in the human SLO3 gene was much higher than in the SLO1 gene (66 versus 43%, respectively). Two other sperm-specific genes that we analyzed (the ion channel CATSPER and the Naϩ/Kϩ-ATPase ␣4) had higher percentages of non-synonymous SNPs (67 and 69%, respectively) than the somatically expressed genes SLO2 and Naϩ/Kϩ-ATPase ␣1 (44 and 40%, respectively) (Fig. 2). This natural structural variation in spermspecific genes may provide a large library of possibilities to achieve a selective advantage in fertilization
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