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

Abstract

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 This work aimed to investigate the role of CaSR in human spermatozoa. Methods We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3′,5′-cyclic adenosine 5′-monophosphate (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 free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3– and the acrosome reaction, whereas 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 Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3– activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas 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 Ca2+, Mg2+, and HCO3– in spermatozoa, and loss-of-function may impair male sperm function.

Alkaline Dilution Alters Sperm Motility in Dairy Goat by Affecting sAC/cAMP/PKA Pathway Activity

“…In spermatozoa, swimming behavior is controlled by rises in Ca 2+ , which change the flagellar beat pattern via Ca 2+ -sensing protein calaxins [ 43 ]. Ca 2+ is required for sAC/cAMP/PKA pathway activation [ 44 ], and Ca 2+ binds to the calmodulin present in the sperm head and flagellum, thus activating other additional phosphorylation cascades regulated by calmodulin kinase as well as the maintenance of sperm mitochondrial functioning and ATP production [ 45 ], which are critical for sperm cell motility.…”

Expression Analysis of ZPB2a and Its Regulatory Role in Sperm-Binding in Viviparous Teleost Black Rockfish

“…The survival and regulation of sperm is a complicated biological process, which is influenced by multiple factors such as Calcium ion concentration, environmental pH value, and surrounding hormone content, etc. [ 31 , 32 , 33 ]. ZP is reported to be mainly active in the sperm through the induction of acrosome reaction in mammals [ 34 ].…”

Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendilines and NPS R-467

“…The asymmetric a-uorination-reductive amination protocol explored above was then extended to buoroamine analogues of the calcimimetic drugs 15-18. Cinacalcet 15 [39] tecalcet 16 [40] fendiline 17 [41] and NPS R-467 18 [42] are agonists which act by allosteric activation of the G-coupled proteincalcium receptor (CaR) [43]. These drugs act essentially by mimicing the role of Ca 2+ ion at the receptor.…”