title: 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 pHiHowever, in human sperm, the major K+conductance is both Ca2+- and pHi-sensitive. It has been debated whether Ca2+-sensitive SLO1 channels substitute for human SLO3 (hSLO3) in human sperm or whether human SLO3 channels have acquired Ca2+sensitivity. Here we show that hSLO3 is rapidly evolving and reveal a natural structural variant with enhanced apparent Ca2+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 Ca2+, 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 Ca2+sensitivities. Whether this physiological variation confers differences in fertility among males remains to be established.
authors.affiliation: the Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Neuroscience.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Ferreira
authors.affiliation: Neuroscience.
authors.forename: Victor
authors.initials: V
authors.lastname: Dzikunu
authors.affiliation: Neuroscience.
authors.forename: Alice
authors.initials: A
authors.lastname: Butler
authors.affiliation: Neuroscience.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lybaert
authors.affiliation: Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and.
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.affiliation: the Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Karl L
authors.initials: KL
authors.lastname: Magleby
authors.affiliation: Neuroscience.|Genetics, and.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Salkoff
authors.affiliation: Neuroscience, santic@wustl.edu.
authors.forename: Celia M
authors.initials: CM
authors.lastname: Santi
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D019143:Evolution, Molecular; D005298:Fertility / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000235:genetics*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism*
chemical_list: C577767:KCNU1 protein, human; C110627:Kcnu1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D002118:Calcium
keywords: calcium sensitivity; fertilization; genetic variant; human SLO3; pH sensitivity; patch clamp; potassium channel; reproduction; sperm; spermatozoa