Complementary role of CNNM2 in sperm motility and Ca(2+) influx during capacitation

Ca(2+) plays a central role in the regulation of sperm motility. We recently reported an unexpected role of CNNM4, a Mg(2+) transporter, in this process by demonstrating perturbed Ca(2+) influx and gradual loss of motility of Cnnm4-deficient sperm. However, Cnnm4-deficient male mice were not entirely infertile, and a significant Ca(2+) response was still observed in their sperm. In the present study, we generated Cnnm4-deficient mice harboring a non-functional Cnnm2 allele (Cnnm2(Δ)), to examine whether CNNM2 compensates for the lost function of CNNM4 in sperm. Cnnm2(+/Δ); Cnnm4(Δ/Δ) mice were infertile, and no obvious histological abnormalities were noted in their testis and epididymis. Their sperm showed normal morphology, but became immotile much more rapidly than those from Cnnm4(Δ/Δ) mice. When capacitation was initiated using serum albumin application, a rapid increase of intracellular Ca(2+) levels was observed in most wild-type sperm, but only about half of sperm from Cnnm4(Δ/Δ) mice exhibited a Ca(2+) response, and the response rate was further reduced in sperm from Cnnm2(+/Δ); Cnnm4(Δ/Δ) mice. Thus, sperm motility and Ca(2+) response were more severely affected in sperm from Cnnm2(+/Δ); Cnnm4(Δ/Δ) mice than in those from Cnnm4(Δ/Δ) mice, implicating CNNM2 in regulating these processes.