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Lyon, M.D.; Ferreira, J.J.; Li, P.; Bhagwat, S.; Butler, A.; Anderson, K.; Polo, M.; Santi, C.M. SLO3. Encyclopedia. Available online: (accessed on 28 November 2023).
Lyon MD, Ferreira JJ, Li P, Bhagwat S, Butler A, Anderson K, et al. SLO3. Encyclopedia. Available at: Accessed November 28, 2023.
Lyon, Maximilian D., Juan J. Ferreira, Ping Li, Shweta Bhagwat, Alice Butler, Kelsey Anderson, Maria Polo, Celia M. Santi. "SLO3" Encyclopedia, (accessed November 28, 2023).
Lyon, M.D., Ferreira, J.J., Li, P., Bhagwat, S., Butler, A., Anderson, K., Polo, M., & Santi, C.M.(2023, July 14). SLO3. In Encyclopedia.
Lyon, Maximilian D., et al. "SLO3." Encyclopedia. Web. 14 July, 2023.

Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the membrane potential to a more negative value. The ion channel responsible for this hyperpolarization, SLO3, was first cloned in 1998, and since then much progress has been made to determine how the channel is regulated and how its function intertwines with various signaling pathways involved in sperm maturation. 

membrane hyperpolarization SLO3 contraception potassium channels sperm acrosomal exocytosis capacitation hyperactivated motility

1. Introduction

Sperm have a long and complex maturation process that completes after they are expelled from the body in which they are produced. This post-ejaculatory process gives sperm the capacity to fertilize an oocyte and thus is termed capacitation [1][2]. Capacitation occurs in the female genital tract and involves many molecular changes including increases in cyclic AMP, protein tyrosine phosphorylation [3], intracellular pH [4][5][6][7], potassium ion (K+) conductance [8], and intracellular calcium (Ca2+) concentration [7][9][10][11][12]. Additionally, the plasma membrane hyperpolarizes to a more negative potential [8][13][14][15][16][17]. These changes culminate in two major physiological changes. The sperm become hyperactive, characterized by an asymmetry of flagellar beating and change in the forces generated [18][19]. This facilitates sperm release from the oviductal reservoir and helps them penetrate through the cumulus and extracellular matrix surrounding the egg (zona pellucida) [20][21]. Additionally, they undergo acrosomal exocytosis, which helps them penetrate the zona pellucida [22][23][24] and exposes binding sites that allow the sperm membrane to fuse with the membrane of the oocyte [25]. Each step of capacitation is required for normal sperm function, but how each step is regulated and regulates other steps has not been fully determined.
A key component of sperm capacitation in many species, from marine invertebrates to mammals, is changes in membrane potential [26][27][28]. Membrane potential is the electrical potential difference (voltage) across a cell’s plasma membrane and is determined by the differences in ion concentrations across the membrane and the selective permeability of the membrane to said ions. One of the most prominent ions for controlling membrane potential in sperm is K+. In 1987, K+-dependent transient membrane hyperpolarization was first reported in sea urchin sperm in response to a signal from the egg jelly [28]. This hyperpolarization was later shown to also occur in murine and bovine sperm and to be associated with capacitation [13]. Like their mammalian counterparts, human sperm undergo a capacitation-associated hyperpolarization from approximately −40 mV [29] to approximately −58 mV [30].
One candidate for the driver of sperm membrane hyperpolarization in mice was SLO3, a potassium channel expressed exclusively in sperm discovered in 1998 [31]. In 2007 a potassium current was identified in mouse sperm that shared several key features with this channel [32]. This current, dubbed IKSper, was found to be activated by intracellular pH. The magnitude of the current meant that it was capable of driving large changes in membrane potential [8][32]. These traits matched those of SLO3, and it was confirmed that SLO3 was responsible for IKSper when a SLO3 knockout mouse was generated [32][33][34][35]. Deletion of SLO3 completely abolished the IKSper current. Additionally, sperm from SLO3 knockout mice lack the hyperpolarization that occurs during capacitation. These sperm also lack the resulting Ca2+ influx through CatSper, the primary Ca2+ channel in sperm that is also necessary for fertility. [33][34]. As a result, SLO3 knockout mice are completely male-infertile.
Several lines of evidence suggest that defects in hyperpolarization can result in human infertility as well. For example, failure to hyperpolarize was correlated with a failure to undergo acrosomal exocytosis in mice [13][27], indicating that sperm membrane hyperpolarization is a key event in sperm capacitation. In humans, electrophysiological studies of patients undergoing in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI) revealed that ~10% of patients with subfertility have depolarized membrane potentials caused by K+ conductance abnormalities [36]. Sperm isolated from men with idiopathic infertility or asthenozoospermia had a significantly more depolarized membrane potential than those from men with normal fertility [37]. Furthermore, capacitated sperm are more hyperpolarized than non-capacitated sperm [26][38]. In 2020, two groups independently used flow cytometry to quantitate membrane potential in sperm from normozoospermic donors and showed that the ability of sperm to hyperpolarize in capacitating conditions correlated with hyperactivation of motility, acrosomal exocytosis, and success in IVF [39][40].
Given the importance of sperm membrane potential in capacitation and fertilization, many researchers have focused on identifying the responsible K+ channels. Two recent papers provide genetic evidence supporting the role of SLO3 in human fertility. Lv et al. reported that a missense mutation and a splice variant of human SLO3 channels are associated with male infertility [41]. However, it should be noted that the male patient in the study presented with asthenozoospermia, a condition characterized by reduced or absent motile sperm [42]. This disorder is not known to be associated with SLO3-deficient mice, as these mice exhibit normal sperm count and motility [33]. Therefore, the presence of this condition suggests that other sperm functional defects unrelated to SLO3 function may have contributed to the infertility observed [41].
In a more compelling case implicating human SLO3 in infertility, a man carrying a missense mutation of the Slo3 gene (c.1237A>T: Ile413Phe) exhibited sperm that failed to hyperpolarize, undergo acrosome reaction, and achieve successful fertilization in in vitro fertilization (IVF) procedures [43]. However, in intracytoplasmic sperm injection (ICSI), where sperm capacitation is not required, fertilization was successful, as expected for a mutation in the Slo3 gene. To further confirm the role of SLO3 in this phenotype, the authors generated a mouse line in which the endogenous Slo3 gene carried the same missense mutation found in the affected men. These mice also exhibited infertility. These findings provide clear evidence that SLO3 is necessary for fertility in both humans and mice and suggest its conserved role in acrosomal exocytosis [43].
A new inhibitor, VU0546110, was recently described which is more than 40-fold selective for human SLO3 over SLO1 [44]. This inhibitor completely inhibited hKSper, confirming that SLO1 channels do not meaningfully contribute to the current. This inhibition also had physiological effects, significantly inhibiting hyperpolarization, hyperactivation, and the acrosome reaction in human sperm. These downstream effects provide further evidence that human SLO3 is necessary for sperm hyperpolarization and fertility.

2. Structure and Gating of the SLO3 Pore-Forming Subunits

The pore-forming components of SLO channels are formed by homo-tetramers of α-subunits. Generally, SLO family α-subunits resemble those of voltage-gated K+ channels in having transmembrane domains symmetrically arranged around a water-filled, K+ selective pore. However, SLO2.1 and SLO2.2 channels have six transmembrane domains (S1–S6) and thus have intracellular N- and C-termini, as is common with members of the voltage-gated K+ channel family [45][46][47]. In contrast, SLO1 and SLO3 have seven transmembrane domains (S0–S6) and thus have extracellular N-termini.
The cytosolic domains of SLO family channels contain two regulators of K+ conductance (RCK) domains, RCK1 and RCK2. These domains sense several intracellular signals and confer each subfamily with distinctive properties [48][49][50][51][52][53]. For example, in SLO1, both RCK1 and RCK2 contain Ca2+ sensors [53][54][55]. The “calcium bowl” in RCK2 is composed of a highly conserved string of aspartate residues, which are negatively charged [56]. SLO2.1 and SLO2.2 are also modulated by Na+, Cl, and activation of G-protein-coupled receptors [45][46][57][58][59][60]. The cytosolic domain may also be a point of interaction between monomers of different SLO family channels.
The gating of SLO3 is similar to that of SLO1, as the opening of both channels is allosterically regulated by movement of a voltage sensor. This movement is driven by transmembrane potential and conformational change of the cytosolic gating ring induced by intracellular ligand binding. However, there are two important differences between the sensitivities of SLO1 and SLO3 channels to ligands. First, SLO1 is activated by acidification, whereas SLO3 is activated by alkalization [31][61]. Second, SLO1 has several Ca2+ binding sites and is activated by a broad range of Ca2+ concentrations [53][56][61]. Because of this, SLO1 can function over a broad range of voltages. In contrast, mouse SLO3 is insensitive to calcium and human SLO3 is several orders of magnitude less sensitive to Ca2+ than SLO1 [62] and functions in a narrow voltage range near the sperm resting potential.
SLO1 and SLO3 are both sensitive to pH. SLO1 has two histidine residues in the gating ring, which may act as proton sensors and open the channel in response to low intracellular pH [61]. The mechanism of pH modulation of SLO3 is unknown. The half-activation point of SLO3 by pH is estimated to be around 7.7 [63], which is close to the pKa of histidine. With the recently solved structures of the human SLO3 gating ring [47] and complete SLO1 channel [64][65][66], the key residues governing SLO3 regulation by protons should be revealed soon.

3. Structure and Function of the SLO3 β and γ Subunits

SLO1 and SLO3 α subunits are associated with several accessory subunits that regulate their expression and biophysical properties [67][68][69]. The α subunit of SLO1 channels is usually associated with auxiliary β- and γ-subunits [70][71][72][73][74], including β1-4 and γ1-2. These auxiliary subunits influence channel pharmacological and gating properties.
An important regulator of SLO3 is γ2, also known as leucine-rich-repeat-containing protein 52 (LRRC52) [75]. This subunit is abundantly expressed in the testis and predominantly interacts with SLO3. It is composed of a single transmembrane segment with an N-terminal extracellular peptide and a short cytoplasmic C-terminal tail [76]. Expression of γ2 depends on SLO3 expression, as Slo3−/− mice do not express measurable γ2. The primary effect of γ2 is to shift the activation of SLO3 to more negative potentials, as seen in mouse, rat, and human channels [47][76][77]. Importantly, mouse SLO3 currents in the presence of γ2 activate at membrane voltage ranges, similar to those of IKSper [76]. The importance of γ2 for SLO3 activity is evident in γ2−/− knockout mice, as IKSper currents in sperm from γ2−/− mice activate more slowly and their activation curve is shifted to more positive potentials than the currents from wild-type sperm. Additionally, alkaline pH is less able to hyperpolarize γ2−/− sperm than wild-type sperm. As a consequence of all this, the γ2−/− male mice are severely subfertile [78], indicating that the γ2 subunit is essential for male fertility.
Mouse and human SLO3 somewhat vary in their responses to γ2. For example, functional expression of human SLO3 requires γ2, and the activation rate and pH sensitivity of human SLO3 channels expressed in Xenopus oocytes are increased by γ2. Although mouse SLO3 can be heterologously expressed without γ2, it has increased expression when this subunit is present [47][62][76][79]. Additionally, mouse SLO3 currents display a minor increase in pH sensitivity and activates at more negative potentials [47] when co-expressed with γ2. Nonetheless, γ2 is an important regulator of mouse SLO3. This was shown by expressing mouse SLO3 in Xenopus oocytes. Currents obtained from expressing mouse SLO3 alone exhibited a different pH- and voltage dependence than IKSper. However, when co-expressed with γ2, SLO3 produced currents that resembled the native IKSper currents [76].
Unlike γ2, γ1 (LRRC26), γ3 (LRRC55), and γ4 (LRRC38) are minimally expressed in the testis [74][76]. Co-expression of γ1 or γ4 with mouse SLO3 in Xenopus oocytes yielded a slight shift towards activation at more negative potentials [76]. Co-expression of γ3 had no effect on mouse or rat SLO3 currents [76]. Thus, γ1, γ3, and γ4 do not appear to play a substantial role in SLO3 regulation.
Because SLO1 is regulated by β subunits, the effects of these subunits on SLO3 have been examined. β1-3 are minimally expressed in the mouse testis and do not appear to functionally regulate SLO3 [72][80][81]. It has even been shown that replacing the mouse SLO1 tail with that of mouse SLO3 ablates the effect of β1 on the channel [82]. Moreover, if co-expressed in Sf9 cells, β1, β3a, and β3b all immunoprecipitate with mouse SLO3 but do not affect the channel gating [81]. β4 is expressed in mouse testis, and co-expression of β4 can increase the surface expression, macro-conductance, and activation kinetics of mouse SLO3 channels in Xenopus oocytes [81]. This indicates that only β4 selectively modulates SLO3 expression and function. In humans, β3 and β4 mRNAs are both expressed in the testis [71], but little is known regarding the effects of β subunits on human SLO3.


  1. Chang, M.C. Fertilizing Capacity of Spermatozoa Deposited into the Fallopian Tubes. Nature 1951, 168, 697–698.
  2. Austin, C. Observations on the Penetration of the Sperm into the Mammalian Egg. Aust. J. Biol. Sci. 1951, 4, 581.
  3. Visconti, P.E.; Moore, G.D.; Bailey, J.L.; Leclerc, P.; Connors, S.A.; Pan, D.; Olds-Clarke, P.; Kopf, G.S. Capacitation of Mouse Spermatozoa. II. Protein Tyrosine Phosphorylation and Capacitation Are Regulated by a CAMP-Dependent Pathway. Development 1995, 121, 1139–1150.
  4. Zeng, Y.; Oberdorf, J.A.; Florman, H.M. PH Regulation in Mouse Sperm: Identification of Na(+)-, Cl(-)-, and HCO3(-)-Dependent and Arylaminobenzoate-Dependent Regulatory Mechanisms and Characterization of Their Roles in Sperm Capacitation. Dev. Biol. 1996, 173, 510–520.
  5. Vredenburgh-Wilberg, W.L.; Parrish, J.J. Intracellular PH of Bovine Sperm Increases during Capacitation. Mol. Reprod. Dev. 1995, 40, 490–502.
  6. Breitbart, H. Signaling Pathways in Sperm Capacitation and Acrosome Reaction. Cell. Mol. Biol. 2003, 49, 321–327.
  7. Ferreira, J.J.; Lybaert, P.; Puga-Molina, L.C.; Santi, C.M. Conserved Mechanism of Bicarbonate-Induced Sensitization of CatSper Channels in Human and Mouse Sperm. Front. Cell Dev. Biol. 2021, 9, 2614.
  8. Chávez, J.C.; de la Vega-Beltrán, J.L.; Escoffier, J.; Visconti, P.E.; Treviño, C.L.; Darszon, A.; Salkoff, L.; Santi, C.M. Ion Permeabilities in Mouse Sperm Reveal an External Trigger for SLO3-Dependent Hyperpolarization. PLoS ONE 2013, 8, e60578.
  9. DasGupta, S.; Mills, C.L.; Fraser, L.R. Ca2+-Related Changes in the Capacitation State of Human Spermatozoa Assessed by a Chlortetracycline Fluorescence Assay. J. Reprod. Fertil. 1993, 99, 135–143.
  10. Baldi, E.; Casano, R.; Falsetti, C.; Krausz, C.; Maggi, M.; Forti, G. Intracellular Calcium Accumulation and Responsiveness to Progesterone in Capacitating Human Spermatozoa. J. Androl. 1991, 12, 323–330.
  11. Chávez, J.C.; Ferreira, J.J.; Butler, A.; De La Vega Beltrán, J.L.; Treviño, C.L.; Darszon, A.; Salkoff, L.; Santi, C.M. SLO3 K+ Channels Control Calcium Entry through CATSPER Channels in Sperm. J. Biol. Chem. 2014, 289, 32266–32275.
  12. Ferreira, J.J.; Cassina, A.; Irigoyen, P.; Ford, M.; Pietroroia, S.; Peramsetty, N.; Radi, R.; Santi, C.M.; Sapiro, R. Increased Mitochondrial Activity upon CatSper Channel Activation Is Required for Mouse Sperm Capacitation. Redox Biol. 2021, 48, 102176.
  13. Zeng, Y.; Clark, E.N.; Florman, H.M. Sperm Membrane Potential: Hyperpolarization during Capacitation Regulates Zona Pellucida-Dependent Acrosomal Secretion. Dev. Biol. 1995, 171, 554–563.
  14. Santi, C.M.; Orta, G.; Salkoff, L.; Visconti, P.E.; Darszon, A.; Treviño, C.L. K+ and Cl− Channels and Transporters in Sperm Function. Curr. Top. Dev. Biol. 2013, 102, 385–421.
  15. Arnoult, C.; Kazam, I.G.; Visconti, P.E.; Kopf, G.S.; Villaz, M.; Florman, H.M. Control of the Low Voltage-Activated Calcium Channel of Mouse Sperm by Egg ZP3 and by Membrane Hyperpolarization during Capacitation. Proc. Natl. Acad. Sci. USA 1999, 96, 6757–6762.
  16. Muñoz-Garay, C.; de la Vega-Beltrán, J.L.; Delgado, R.; Labarca, P.; Felix, R.; Darszon, A. Inwardly Rectifying K+ Channels in Spermatogenic Cells: Functional Expression and Implication in Sperm Capacitation. Dev. Biol. 2001, 234, 261–274.
  17. Gunderson, S.J.; Puga Molina, L.C.; Spies, N.; Balestrini, P.A.; Buffone, M.G.; Jungheim, E.S.; Riley, J.; Santi, C.M. Machine-Learning Algorithm Incorporating Capacitated Sperm Intracellular PH Predicts Conventional in Vitro Fertilization Success in Normospermic Patients. Fertil. Steril. 2021, 115, 930–939.
  18. Mortimer, S.T.; Swan, M.A.; Mortimer, D. Effect of Seminal Plasma on Capacitation and Hyperactivation in Human Spermatozoa. Human. Reprod. 1998, 13, 2139–2146.
  19. Ishijima, S. Dynamics of Flagellar Force Generated by a Hyperactivated Spermatozoon. Reproduction 2011, 142, 409–415.
  20. Demott, R.P.; Suarez, S.S. Hyperactivated Sperm Progress in the Mouse Oviduct. Biol. Reprod. 1992, 46, 779–785.
  21. Suarez, S.S.; Dai, X.B.; DeMott, R.P.; Redfern, K.; Mirando, M.A. Movement Characteristics of Boar Sperm Obtained from the Oviduct or Hyperactivated in vitro. J. Androl. 1992, 13, 75–80.
  22. Yanagimachi, R. Fertility of Mammalian Spermatozoa: Its Development and Relativity. Zygote 1994, 2, 371–372.
  23. Buffone, M.G.; Rodriguez-Miranda, E.; Storey, B.T.; Gerton, G.L. Acrosomal Exocytosis of Mouse Sperm Progresses in a Consistent Direction in Response to Zona Pellucida. J. Cell Physiol. 2009, 220, 611–620.
  24. Breitbart, H.; Rubinstein, S.; Lax, Y. Regulatory Mechanisms in Acrosomal Exocytosis. Rev. Reprod. 1997, 2, 165–174.
  25. Inoue, N.; Ikawa, M.; Okabe, M. The Mechanism of Sperm–Egg Interaction and the Involvement of IZUMO1 in Fusion. Asian J. Androl. 2011, 13, 81.
  26. López-González, I.; Torres-Rodríguez, P.; Sánchez-Carranza, O.; Solís-López, A.; Santi, C.M.; Darszon, A.; Treviño, C.L. Membrane Hyperpolarization during Human Sperm Capacitation. Mol. Hum. Reprod. 2014, 20, 619–629.
  27. De La Vega-Beltran, J.L.; Sánchez-Cárdenas, C.; Krapf, D.; Hernandez-González, E.O.; Wertheimer, E.; Treviño, C.L.; Visconti, P.E.; Darszon, A. Mouse Sperm Membrane Potential Hyperpolarization Is Necessary and Sufficient to Prepare Sperm for the Acrosome Reaction. J. Biol. Chem. 2012, 287, 44384–44393.
  28. González-Martínez, M.; Darszon, A. A Fast Transient Hyperpolarization Occurs during the Sea Urchin Sperm Acrosome Reaction Induced by Egg Jelly. FEBS Lett. 1987, 218, 247–250.
  29. Linares-Hernández, L.; Guzmán-Grenfell, A.M.; Hicks-Gomez, J.J.; González-Martínez, M.T. Voltage-Dependent Calcium Influx in Human Sperm Assessed by Simultaneous Optical Detection of Intracellular Calcium and Membrane Potential. Biochim. Biophys. Acta Biomembr. 1998, 1372, 1–12.
  30. Patrat, C.; Serres, C.; Jouannet, P. Progesterone Induces Hyperpolarization after a Transient Depolarization Phase in Human Spermatozoa. Biol. Reprod. 2002, 66, 1775–1780.
  31. Schreiber, M.; Wei, A.; Yuan, A.; Gaut, J.; Saito, M.; Salkoff, L. Slo3, a Novel PH-Sensitive K+ Channel from Mammalian Spermatocytes. J. Biol. Chem. 1998, 273, 3509–3516.
  32. Navarro, B.; Kirichok, Y.; Clapham, D.E. KSper, a PH-Sensitive K+ Current That Controls Sperm Membrane Potential. Proc. Natl. Acad. Sci. USA 2007, 104, 7688–7692.
  33. Santi, C.M.; Martínez-López, P.; de la Vega-Beltrán, J.L.; Butler, A.; Alisio, A.; Darszon, A.; Salkoff, L. The SLO3 Sperm-Specific Potassium Channel Plays a Vital Role in Male Fertility. FEBS Lett. 2010, 584, 1041–1046.
  34. Zeng, X.H.; Yang, C.; Kim, S.T.; Lingle, C.J.; Xia, X.M. Deletion of the Slo3 Gene Abolishes Alkalization-Activated K+ Current in Mouse Spermatozoa. Proc. Natl. Acad. Sci. USA 2011, 108, 5879–5884.
  35. Zeng, X.H.; Navarro, B.; Xia, X.M.; Clapham, D.E.; Lingle, C.J. Simultaneous Knockout of Slo3 and CatSper1 Abolishes All Alkalization- and Voltage-Activated Current in Mouse Spermatozoa. J. Gen. Physiol. 2013, 142, 305–313.
  36. Brown, S.G.; Publicover, S.J.; Mansell, S.A.; Lishko, P.V.; Williams, H.L.; Ramalingam, M.; Wilson, S.M.; Barratt, C.L.R.; Sutton, K.A.; Da Silva, S.M. Depolarization of Sperm Membrane Potential Is a Common Feature of Men with Subfertility and Is Associated with Low Fertilization Rate at IVF. Human. Reprod. 2016, 31, 1147–1157.
  37. Calzada, L.; Tellez, J. Defective Function of Membrane Potential (Ψ) on Sperm of Infertile Men. Arch. Androl. 1997, 38, 151–155.
  38. Brukman, N.G.; Nuñez, S.Y.; Puga Molina, L.d.C.; Buffone, M.G.; Darszon, A.; Cuasnicu, P.S.; Da Ros, V.G. Tyrosine Phosphorylation Signaling Regulates Ca2+ Entry by Affecting Intracellular PH during Human Sperm Capacitation. J. Cell Physiol. 2019, 234, 5276–5288.
  39. Molina, L.C.P.; Gunderson, S.; Riley, J.; Lybaert, P.; Borrego-Alvarez, A.; Jungheim, E.S.; Santi, C.M. Membrane Potential Determined by Flow Cytometry Predicts Fertilizing Ability of Human Sperm. Front. Cell Dev. Biol. 2020, 7, 387.
  40. Baro Graf, C.; Ritagliati, C.; Torres-Monserrat, V.; Stival, C.; Carizza, C.; Buffone, M.G.; Krapf, D. Membrane Potential Assessment by Fluorimetry as a Predictor Tool of Human Sperm Fertilizing Capacity. Front. Cell Dev. Biol. 2020, 7, 383.
  41. Lv, M.; Liu, C.; Ma, C.; Yu, H.; Shao, Z.; Gao, Y.; Liu, Y.; Wu, H.; Tang, D.; Tan, Q.; et al. Homozygous Mutation in SLO3 Leads to Severe Asthenoteratozoospermia Due to Acrosome Hypoplasia and Mitochondrial Sheath Malformations. Reprod. Biol. Endocrinol. 2022, 20, 1–15.
  42. Cavarocchi, E.; Whitfield, M.; Saez, F.; Touré, A. Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives. Int. J. Mol. Sci. 2022, 23, 3926.
  43. Liu, R.; Yan, Z.; Fan, Y.; Qu, R.; Chen, B.; Li, B.; Wu, L.; Wu, H.; Mu, J.; Zhao, L.; et al. Bi-Allelic Variants in KCNU1 Cause Impaired Acrosome Reactions and Male Infertility. Hum. Reprod. 2022, 37, 1394–1405.
  44. Lyon, M.; Li, P.; Ferreira, J.J.; Lazarenko, R.M.; Kharade, S.V.; Kramer, M.; McClenahan, S.J.; Days, E.; Bauer, J.A.; Spitznagel, B.D.; et al. A Selective Inhibitor of the Sperm-Specific Potassium Channel SLO3 Impairs Human Sperm Function. Proc. Natl. Acad. Sci. USA 2023, 120, e2212338120.
  45. Bhattacharjee, A.; Joiner, W.J.; Wu, M.; Yang, Y.; Sigworth, F.J.; Kaczmarek, L.K. Slick (Slo2.1), a Rapidly-Gating Sodium-Activated Potassium Channel Inhibited by ATP. J. Neurosci. 2003, 23, 11681–11691.
  46. Yuan, A.; Santi, C.M.; Wei, A.; Wang, Z.W.; Pollak, K.; Nonet, M.; Kaczmarek, L.; Crowder, C.M.; Salkoff, L. The Sodium-Activated Potassium Channel Is Encoded by a Member of the Slo Gene Family. Neuron 2003, 37, 765–773.
  47. Leonetti, M.D.; Yuan, P.; Hsiung, Y.; MacKinnon, R. Functional and Structural Analysis of the Human SLO3 PH- and Voltage-Gated K+ Channel. Proc. Natl. Acad. Sci. USA 2012, 109, 19274–19279.
  48. Jiang, Y.; Pico, A.; Cadene, M.; Chait, B.T.; MacKinnon, R. Structure of the RCK Domain from the E. Coli K+ Channel and Demonstration of Its Presence in the Human BK Channel. Neuron 2001, 29, 593–601.
  49. Peng, Y.; Leonetti, M.D.; Pico, A.R.; Hsiung, Y.; MacKinnon, R. Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 Å Resolution. Science 2010, 329, 182–186.
  50. Marty, A. Ca-Dependent K Channels with Large Unitary Conductance in Chromaffin Cell Membranes. Nature 1981, 291, 497–500.
  51. Pallotta, B.S.; Magleby, K.L.; Barrett, J.N. Single Channel Recordings of Ca2+-Activated K+ Currents in Rat Muscle Cell Culture. Nature 1981, 293, 471–474.
  52. Latorre, R.; Vergara, C.; Hidalgo, C. Reconstitution in Planar Lipid Bilayers of a Ca2+-Dependent K+ Channel from Transverse Tubule Membranes Isolated from Rabbit Skeletal Muscle. Proc. Natl. Acad. Sci. USA 1982, 79, 805–809.
  53. Schreiber, M.; Yuan, A.; Salkoff, L. Transplantable Sites Confer Calcium Sensitivity to BK Channels. Nat. Neurosci. 1999, 2, 416–421.
  54. Xia, X.M.; Zeng, X.; Lingle, C.J. Multiple Regulatory Sites in Large-Conductance Calcium-Activated Potassium Channels. Nature 2002, 418, 880–884.
  55. Geng, Y.; Deng, Z.; Zhang, G.; Budelli, G.; Butler, A.; Yuan, P.; Cui, J.; Salkoff, L.; Magleby, K.L. Coupling of Ca2+ and Voltage Activation in BK Channels through the AB Helix/Voltage Sensor Interface. Proc. Natl. Acad. Sci. USA 2020, 117, 14512–14521.
  56. Schreiber, M.; Salkoff, L. A Novel Calcium-Sensing Domain in the BK Channel. Biophys. J. 1997, 73, 1355–1363.
  57. Santi, C.M.; Ferreira, G.; Yang, B.; Gazula, V.-R.; Butler, A.; Wei, A.; Kaczmarek, L.K.; Salkoff, L. Opposite Regulation of Slick and Slack K Channels by Neuromodulators. J. Neurosci. 2006, 26, 5059–5068.
  58. Li, P.; Halabi, C.M.; Stewart, R.; Butler, A.; Brown, B.; Xia, X.; Santi, C.; England, S.; Ferreira, J.; Mecham, R.P.; et al. Sodium-Activated Potassium Channels Moderate Excitability in Vascular Smooth Muscle. J. Physiol. 2019, 597, 5093–5108.
  59. Ferreira, J.J.; Butler, A.; Stewart, R.; Gonzalez-Cota, A.L.; Lybaert, P.; Amazu, C.; Reinl, E.L.; Wakle-Prabagaran, M.; Salkoff, L.; England, S.K.; et al. Oxytocin Can Regulate Myometrial Smooth Muscle Excitability by Inhibiting the Na+-Activated K+ Channel, Slo2.1. J. Physiol. 2019, 597, 137–149.
  60. Bhattacharjee, A.; Gan, L.; Kaczmarek, L.K. Localization of the Slack Potassium Channel in the Rat Central Nervous System. J. Comp. Neurol. 2002, 454, 241–254.
  61. Hou, S.; Xu, R.; Heinemann, S.H.; Hoshi, T. Reciprocal Regulation of the Ca2+ and H+ Sensitivity in the SLO1 BK Channel Conferred by the RCK1 Domain. Nat. Struct. Mol. Biol. 2008, 15, 403–410.
  62. Brenker, C.; Zhou, Y.; Muller, A.; Echeverry, F.A.; Trotschel, C.; Poetsch, A.; Xia, X.M.; Bonigk, W.; Lingle, C.J.; Kaupp, U.B.; et al. The Ca2+-Activated K+ Current of Human Sperm Is Mediated by Slo3. Elife 2014, 2014, e01438.
  63. Zhang, X.; Zeng, X.; Lingle, C.J. Slo3 K+ Channels: Voltage and PH Dependence of Macroscopic Currents. J. Gen. Physiol. 2006, 128, 317–336.
  64. Hite, R.K.; Tao, X.; MacKinnon, R. Structural Basis for Gating the High-Conductance Ca2+-Activated K+ Channel. Nature 2017, 541, 52–57.
  65. Tao, X.; Hite, R.K.; MacKinnon, R. Cryo-EM Structure of the Open High-Conductance Ca2+-Activated K+ Channel. Nature 2017, 541, 46–51.
  66. Tao, X.; Mackinnon, R. Molecular Structures of the Human Slo1 K+ Channel in Complex with B4. eLife 2019, 8, e51409.
  67. Liu, G.; Niu, X.; Wu, R.S.; Chudasama, N.; Yao, Y.; Jin, X.; Weinberg, R.; Zakharov, S.I.; Motoike, H.; Marx, S.O.; et al. Location of Modulatory β Subunits in BK Potassium Channels. J. Gen. Physiol. 2010, 135, 449–459.
  68. Chen, G.; Li, Q.; Yan, J. The Leucine-Rich Repeat Domains of BK Channel Auxiliary γ Subunits Regulate Their Expression, Trafficking, and Channel-Modulation Functions. J. Biol. Chem. 2022, 298, 101664.
  69. Gonzalez-Perez, V.; Xia, X.-M.; Lingle, C.J. Functional Regulation of BK Potassium Channels by Γ1 Auxiliary Subunits. Proc. Natl. Acad. Sci. USA 2014, 111, 4868–4873.
  70. Behrens, R.; Nolting, A.; Reimann, F.; Schwarz, M.; Waldscḧtz, R.; Pongs, O. HKCNMB3 and HKCNMB4, Cloning and Characterization of Two Members of the Large-Conductance Calcium-Activated Potassium Channel β Subunit Family. FEBS Lett. 2000, 474, 99–106.
  71. Brenner, R.; Jegla, T.J.; Wickenden, A.; Liu, Y.; Aldrich, R.W. Cloning and Functional Characterization of Novel Large Conductance Calcium-Activated Potassium Channel β Subunits, HKCNMB3 and HKCNMB4. J. Biol. Chem. 2000, 275, 6453–6461.
  72. Uebele, V.N.; Lagrutta, A.; Wade, T.; Figueroa, D.J.; Liu, Y.; McKenna, E.; Austin, C.P.; Bennett, P.B.; Swanson, R. Cloning and Functional Expression of Two Families of β-Subunits of the Large Conductance Calcium-Activated K+ Channel. J. Biol. Chem. 2000, 275, 23211–23218.
  73. Yan, J.; Aldrich, R.W. LRRC26 Auxiliary Protein Allows BK Channel Activation at Resting Voltage without Calcium. Nature 2010, 466, 513–516.
  74. Yan, J.; Aldrich, R.W. BK Potassium Channel Modulation by Leucine-Rich Repeat-Containing Proteins. Proc. Natl. Acad. Sci. USA 2012, 109, 7917–7922.
  75. Dolan, J.; Walshe, K.; Alsbury, S.; Hokamp, K.; O’Keeffe, S.; Okafuji, T.; Miller, S.F.C.; Tear, G.; Mitchell, K.J. The Extracellular Leucine-Rich Repeat Superfamily; a Comparative Survey and Analysis of Evolutionary Relationships and Expression Patterns. BMC Genom. 2007, 8, 1–24.
  76. Yang, C.; Zeng, X.-H.; Zhou, Y.; Xia, X.-M.; Lingle, C.J. LRRC52 (Leucine-Rich-Repeat-Containing Protein 52), a Testis-Specific Auxiliary Subunit of the Alkalization-Activated Slo3 Channel. Proc. Natl. Acad. Sci. USA 2011, 108, 19419–19424.
  77. Wang, G.M.; Zhong, Z.G.; Du, X.R.; Zhang, F.F.; Guo, Q.; Liu, Y.; Tang, Q.Y.; Zhang, Z. Cloning and Characterization of the Rat Slo3 (KCa5.1) Channel: From Biophysics to Pharmacology. Br. J. Pharmacol. 2020, 177, 3552–3567.
  78. Zeng, X.-H.; Yang, C.; Xia, X.-M.; Liu, M.; Lingle, C.J. SLO3 Auxiliary Subunit LRRC52 Controls Gating of Sperm KSPER Currents and Is Critical for Normal Fertility. Proc. Natl. Acad. Sci. USA 2015, 112, 2599–2604.
  79. Sánchez-Carranza, O.; Torres-Rodríguez, P.; Darszon, A.; Treviño, C.L.; López-González, I. Pharmacology of HSlo3 Channels and Their Contribution in the Capacitation-Associated Hyperpolarization of Human Sperm. Biochem. Biophys. Res. Commun. 2015, 466, 554–559.
  80. Jiang, Z.; Wallner, M.; Meera, P.; Toro, L. Human and Rodent MaxiK Channel β-Subunit Genes: Cloning and Characterization. Genomics 1999, 55, 57–67.
  81. Yang, C.-T.; Zeng, X.-H.; Xia, X.-M.; Lingle, C.J. Interactions between β Subunits of the KCNMB Family and Slo3: Β4 Selectively Modulates Slo3 Expression and Function. PLoS ONE 2009, 4, e6135.
  82. Qian, X.; Nimigean, C.M.; Niu, X.; Moss, B.L.; Magleby, K.L. Slo1 Tail Domains, but Not the Ca2+ Bowl, Are Required for the Β1 Subunit to Increase the Apparent Ca2+ Sensitivity of BK Channels. J. Gen. Physiol. 2002, 120, 829–843.
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