The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa

Area of Science:

• Reproductive Biology
• Sperm Physiology
• Sperm Function

Background:

• The calcium-sensing receptor (CaSR) maintains serum calcium homeostasis.
• Spermatozoa encounter varying CaSR ligand concentrations during maturation and in the female reproductive tract.
• The role of CaSR in human spermatozoa remains largely unexplored.

Purpose of the Study:

• To investigate the presence and function of CaSR in human spermatozoa.
• To characterize the effects of CaSR activation on sperm function, including intracellular calcium levels, acrosome reaction, and cAMP production.
• To examine the impact of CaSR mutations on male reproductive parameters.

Main Methods:

• CaSR identification in human spermatozoa.
• Assessment of CaSR agonist responses on intracellular calcium, acrosome reaction, and cAMP.
• Analysis of spermatozoa from individuals with CaSR loss-of-function or gain-of-function mutations and healthy donors.

Main Results:

• CaSR is expressed in human spermatozoa, sensing extracellular Ca2+ and Mg2+.
• CaSR activation enhances sperm responses to bicarbonate and augments the acrosome reaction.
• Loss-of-function CaSR mutations diminish responses to bicarbonate, reduce progesterone-mediated calcium influx, and impair the acrosome reaction.
• CaSR activation increases cAMP via soluble adenylyl cyclase (sAC) and calcium influx via CatSper.
• External Ca2+ and Mg2+ are essential for bicarbonate-induced sAC activation.
• CASR mutations can correlate with impaired sperm count, motility, and morphology.

Conclusions:

• CaSR plays a critical role in sensing Ca2+, Mg2+, and bicarbonate in human spermatozoa.
• CaSR dysfunction can significantly impair male sperm function and reproductive health.