The Calcium-Sensing Receptor and the Reproductive System

Abstract

Active placental transport of maternal serum calcium (Ca2+) to the offspring is pivotal for proper development of the fetal skeleton as well as various organ systems. Moreover, extracellular Ca2+ levels impact on distinct processes in mammalian reproduction. The calcium-sensing receptor (CaSR) translates changes in extracellular Ca2+-concentrations into cellular reactions. This review summarizes current knowledge on the expression of CaSR and its putative functions in reproductive organs. CaSR was detected in placental cells mediating materno-fetal Ca2+-transport such as the murine intraplacental yolk sac (IPYS) and the human syncytiotrophoblast. As shown in casr knock-out mice, ablation of CaSR downregulates transplacental Ca2+-transport. Receptor expression was reported in human and rat ovarian surface epithelial (ROSE) cells, where CaSR activation stimulates cell proliferation. In follicles of various species a role of CaSR activation in oocyte maturation was suggested. Based on studies in avian follicles, the activation of CaSR expressed in granulosa cells may support the survival of follicles after their selection. CaSR in rat and equine sperms was functionally linked to sperm motility and sperm capacitation. Implantation involves complex interactions between the blastocyst and the uterine epithelium. During early pregnancy, CaSR expression at the implantation site as well as in decidual cells indicates that CaSR is important for blastocyst implantation and decidualization in the rat uterus. Localization of CaSR in human extravillous cytotrophoblasts suggests a role of CaSR in placentation. Overall, evidence for functional involvement of CaSR in physiologic mammalian reproductive processes exists. Moreover, several studies reported altered expression of CaSR in cells of reproductive tissues under pathologic conditions. However, in many tissues we still lack knowledge on physiological ligands activating CaSR, CaSR-linked G-proteins, activated intracellular signaling pathway, and functional relevance of CaSR activation. Clearly, more work is required in the future to decode the complex physiologic and pathophysiologic relationship of CaSR and the mammalian reproductive system.

Insights into pH regulatory mechanisms in mediating spermatozoa functions

“…Intracellular pH also regulates the opening of sperm-specific Ca ++ channel (CatSper) in sperm flagella, and this is the major ion channel that regulates sperm intracellular Ca ++ . Processes such as sperm hyperactivation, capacitation, and acrosome reaction are also associated with intracellular Ca ++ fluxing through CatSper channels [ 17 , 18 ]. Pharmacological and electrophysiological studies have revealed the precise role of pH (H + ) in regulation as well as activation of CatSper channels and thereby regulation of intracellular Ca ++ .…”

Calcium-Sensing Receptor Internalization Isβ-Arrestin–Dependent and Modulated by Allosteric Ligands

“…Recently, the CaSR PAM etelcalcetide received regulatory approval for clinical use as a more efficacious alternative for cinacalcet with a higher level of compliance (Block et al, 2017;Patel and Bridgeman, 2018;Xipell et al, 2019). CaSR expression in tissues unrelated to calcium homeostasis suggests that this receptor could also be a potential therapeutic target for cardiovascular diseases, infertility, and cancer (Ellinger, 2016;Tennakoon et al, 2016;Guo et al, 2018). Nevertheless, the precise contribution of the CaSR in these disease contexts remains uncertain.…”

The calcium‐sensing receptor regulates protein tyrosine phosphorylation through PDK1 in boar spermatozoa

“…One of its physiological meaning could be that, in the female tract, different stimuli and/or ligands would be preventing premature capacitation (Figure a), the inhibition of CaSR could be a signal initiating the capacitation process (Figure b). In this regard, it has to be mentioned that a wide variety of modulators of CaSR such us calcium, magnesium, polyamines, aromatic l ‐amino acids, ionic strength, changing pH, among others (Ellinger, ; Saidak, Brazier, Kamel, & Mentaverri, ) are present in the female tract and could be modulating sperm capacitation, or even other functions as motility, through CaSR.…”

“…In mammalian gametes different studies have been carried out to elucidate the role of this receptor, demonstrating its importance in the fertilization process (Ellinger, 2016). Specifically, CaSR is implicated in bovine embryo development (Macías-García, Lopes, Rocha, & González-Fernández, 2017) and in the regulation of oocyte maturation in horses (De Santis et al, 2009) and pigs (Liu et al, 2015); additionally, it has been shown to play a role in porcine in vitro fertilization and early embryo development (Liu, Liu, Larsen, Hou, & Callesen, 2018).…”