A genetic variant of the sperm-specific SLO3 K+ channel has altered pH and Ca2+ sensitivities

Abstract

To fertilize an oocyte, sperm must first undergo capacitation in which the sperm plasma membrane becomes hyperpolarized via activation of potassium (K) channels and resultant K efflux. Sperm-specific SLO3 K channels are responsible for these membrane potential changes critical for fertilization in mouse sperm, and they are only sensitive to pH However, in human sperm, the major K conductance is both Ca- and pH -sensitive. It has been debated whether Ca-sensitive SLO1 channels substitute for human SLO3 (hSLO3) in human sperm or whether human SLO3 channels have acquired Ca sensitivity. Here we show that hSLO3 is rapidly evolving and reveal a natural structural variant with enhanced apparent Ca and pH sensitivities. This variant allele (C382R) alters an amino acid side chain at a principal interface between the intramembrane-gated pore and the cytoplasmic gating ring of the channel. Because the gating ring contains sensors to intracellular factors such as pH and Ca, the effectiveness of transduction between the gating ring and the pore domain appears to be enhanced. Our results suggest that sperm-specific genes can evolve rapidly and that natural genetic variation may have led to a SLO3 variant that differs from wild type in both pH and intracellular Ca sensitivities. Whether this physiological variation confers differences in fertility among males remains to be established.

Elucidating the Role of K+ Channels during In Vitro Capacitation of Boar Spermatozoa: Do SLO1 Channels Play a Crucial Role?

“…These channels, which belong to the SLO gene family [2,3,9,11,12], have been reported to play a vital role in the regulation of sperm volume, and have also been found to be involved in the sequence of changes that take place during capacitation [2,9,13]. Remarkably, whereas such a regulating role is mainly performed by SLO3 in mouse [1,11,12,14], it involves both SLO1 [2] and SLO3 [3] in human spermatozoa. SLO1 channels or big potassium (BK) or maxi K + channels, exhibit high sensitivity to changes of both voltage and intracellular Ca 2+ levels [15,16], whereas SLO3 channels are highly sensitive to intracellular alkalinization [9].…”

+mRNA expression of LRRC55 protein (leucine-rich repeat-containing protein 55) in the adult mouse brain

“…Slo1 channels are Ca 2+ activated potassium channels while Slo2 channels are gated by sodium [ 8 , 9 ]. Slo3 channels are specifically expressed in testis and activated by alkalization [ 10 , 11 , 12 ]. Slo1 channels are also regulated by β1 to β4 subunits, which confer slow activation time course and/or inactivation character to Slo1 channels [ 13 , 14 , 15 ].…”

TRPV4 is the temperature-sensitive ion channel of human sperm

“…In human spermatozoa, K + , Ca 2+ , Cl – , and H + conductances have been described ( Lishko et al, 2011 ; Strünker et al, 2011 ; Smith et al, 2013 ; Lishko et al, 2010 ; Berger et al, 2017 ; Mannowetz et al, 2013 ; Brenker et al, 2014 ; Brown et al, 2016 ; Geng et al, 2017 ; Williams et al, 2015 ; Orta et al, 2012 ). However, the molecular nature of Na + conductance of sperm remained unknown.…”