The calcium-sensing receptor is essential for calcium and bicarbonate sensitivity in human spermatozoa.

Context The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown. Objective and design We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and cAMP in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors. Results CaSR is expressed in human spermatozoa and is essential for sensing extracellular Ca 2+ and Mg 2+. Activators of CaSR augmented the effect of sperm activating signals such as the response to HCO3- and the acrosome reaction, while spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3-, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca 2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca 2+ or Mg 2+ was indispensable for HCO3- activation of sAC. Two male patients with CASR loss-of-function mutation in exon 3 present with normal sperm counts and motility, while a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology. Conclusion CaSR is important for the sensing of Ca 2+, Mg 2+, and HCO3 - in spermatozoa, and loss-of-function may impair male sperm function.