2.A.36.7.5
Sodium/hydrogen exchanger 10 (Na⁺/H⁺ exchanger 10) (NHE-10) (Solute carrier family 9 member 10) (Solute carrier family 9 member C1) (Sperm-specific Na⁺/H⁺ exchanger) (sNHE).  It is predicted to have 17 TMSs in a 13 +  4 TMS arrangement.  The last 4 TMSs are homologous to the 4 TMS voltage sensor of the Ca²⁺ channel, 1.A.1.11.7. sNHE is a target for inhibition, for use in male contraception, causing inhibition of sperm motility (Mariani et al. 2023). Ion currents through the voltage sensor domains (VSDs) of distinct families of proteins have been studied (Arcos-Hernández and Nishigaki 2023).  The VSD confers voltage sensitivity to different types of transmembrane proteins such as (1) voltage-gated ion channels, (2) the voltage-sensing phosphatase (Ci-VSP), and (3) this sperm-specific Na⁺/H⁺ exchanger (sNHE). VSDs contain four TMSs (S1-S4) and several positively charged amino acids in S4, which are essential for the voltage sensitivity of the protein. Generally, in response to changes in the V_m, the positive residues of S4 displace along the plasma membrane without generating ionic currents through this domain. However, some native (e.g., Hv1 channels) and mutants of VSDs produce ionic currents. These gating pore currents are usually observed in VSDs that lack one or more of the conserved positively charged amino acids in S4. The gating pore currents can also be induced by the isolation of a VSD from the rest of the protein domains. Arcos-Hernández and Nishigaki 2023 summarized gating pore currents from all families of proteins with VSDs with classification into three cases: (1) pathological, (2) physiological, and (3) artificial currents.  SLC9C1, underlies hyperpolarization and cyclic nucleotide stimulated proton fluxes across sperm membranes and regulates their hyperactivated motility. It is the first known instance of an ion transporter that uses a canonical voltage-sensing domain (VSD) and an evolutionarily conserved cyclic nucleotide binding domain (CNBD) to influence the dynamics of its ion-exchange domain (ED) (Chowdhury and Pal 2023).  Binding of cAMP causes large conformational changes in the cytoplasmic domains and disrupts key ARD-linked interfaces. These structural changes rescue the transmembrane domains from an auto-inhibited state and facilitate their functional dynamics (Chowdhury and Pal 2023).