Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel, mutations of which cause cystic fibrosis, a disease characterized by defective Cl ؊ and HCO3 ؊ transport. Although >95% of all CF male patients are infertile because of congenital bilateral absence of the vas deferens (CBAVD), the question whether CFTR mutations are involved in other forms of male infertility is under intense debates. Here we report that CFTR is detected in both human and mouse sperm. CFTR inhibitor or antibody significantly reduces the sperm capacitation, and the associated HCO 3 ؊ -dependent events, including increases in intracellular pH, cAMP production and membrane hyperpolarization. The fertilizing capacity of the sperm obtained from heterozygous CFTR mutant mice is also significantly lower compared with that of the wild-type. These results suggest that CFTR in sperm may be involved in the transport of HCO 3 ؊ important for sperm capacitation and that CFTR mutations with impaired CFTR function may lead to reduced sperm fertilizing capacity and male infertility other than CBAVD.

Male infertility: Pathogenesis and clinical diagnosis

“…14 Some studies from the late 90's suggested an association between CFTR mutation and defective testicular function, however latest data based on an extensive CFTR analysis in infertile individuals versus well selected fertile population definitively excludes the involvement of the CFTR gene variants in sperm production. 15 In a mouse model, Xu et al 16 demonstrated that CFTR protein is also involved in HCO3-membrane transport which is essential for sperm capacitation and thus for sperm fertilizing ability. These data suggest a possible role for CFTR mutations in the etiology of unexplained couple infertility but it requires further confirmation.…”

CFTR mediates bicarbonate-dependent activation of miR-125b in preimplantation embryo development

“…Next, we set out to explore the signaling mechanism involved. Since HCO 3 − is an activator of sAC, the effect of CFTR-mediated HCO 3 − influx on miR-125b expression and embryo development may be mediated by sAC and its downstream cAMP/PKAdependent pathway [28,38]. We therefore tested the involvement of sAC and PKA in HCO 3 − -dependent embryo development.…”

“…The effect of HCO 3 − in triggering downstream signaling requires CFTR (cystic fibrosis transmembrane conductance regulator), a cAMP-activated anion channel known to conduct Cl − [29,30] and HCO 3 − [31], as the necessary HCO 3 − transport mechanism, either directly or indirectly [28,32]. This suggests that high HCO 3 − concentration may act as an environmental stimulus in initiating cellular responses through CFTR-mediated entry.…”

“…We have previously demonstrated that HCO 3 − -rich uterine environment triggers sperm capacitation [28], a process by which sperms acquire their fertilizing capacity. The effect of HCO 3 − in triggering downstream signaling requires CFTR (cystic fibrosis transmembrane conductance regulator), a cAMP-activated anion channel known to conduct Cl − [29,30] and HCO 3 − [31], as the necessary HCO 3 − transport mechanism, either directly or indirectly [28,32].…”

Activation of GABAAReceptor/Cl−Channel and Capacitation in Rat Spermatozoa: HCO3−and Cl−are Essential

“…In addition, it is known that Cl À and its channels play important roles in the maintenance of sperm cellular volume [Yeung et al 2004], intracellular pH [Zeng et al 1996], resting membrane potential and excitability [Chan et al 1997;Zhang and Shi 1998]. For example, the sperm cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl À channel which is involved in the transport of HCO 3 À that is important for sperm capacitation and fertilization [Hernandez-Gonzalez et al 2007;Xu et al 2007]. In addition, Cl À has been reported to be required for the progesterone-, GABA-and zona pellucid-initiated acrosome reaction in mouse, porcine, hamster and human spermatozoa [Espinosa et al 1998;Melendrez and Meizel 1995;Shi et al 1997;Wistrom and Meizel 1993;Yashimatsu and Yanagimachi 1988].…”