Abstract
Voltage-sensing (VSD) and cyclic nucleotide-binding domains (CNBD) gate ion channels for rapid electrical signaling. By contrast, solute carriers (SLCs) that passively redistribute substrates are gated by their substrates themselves. Here, we study the orphan sperm-specific solute carriers SLC9C1 that feature a unique tripartite structure: an exchanger domain, a VSD, and a CNBD. Voltage-clamp fluorimetry shows that SLC9C1 is a genuine Na+/H+ exchanger gated by voltage. The cellular messenger cAMP shifts the voltage range of activation. Mutations in the transport domain, the VSD, or the CNBD strongly affect Na+/H+ exchange, voltage gating, or cAMP sensitivity, respectively. Our results establish SLC9C1 as a phylogenetic chimaera that combines the ion-exchange mechanism of solute carriers with the gating mechanism of ion channels. Classic SLCs slowly readjust changes in the intra- and extracellular milieu, whereas voltage gating endows the Na+/H+ exchanger with the ability to produce a rapid pH response that enables downstream signaling events.
Highlights
Changes in pHi are key to sperm signaling[3,4,5,6,7,8,9,10,11], but it is not known if SLC9C1 promotes Na+/H+ exchange, how its activity is controlled, and whether it contributes to pHi regulation
SLC9C1 holds a putative voltage-sensing domain (VSD) and a putative cyclic nucleotide-binding domain (CNBD) that are absent in other SLC9 members (Fig. 1a)
All but one of the important Na+-coordinating residues are conserved in SpSLC9C1, including an Asn/Asp motif (Asn237/Asp238) that is diagnostic for electroneutral exchangers[24] (Fig. 1a, b)
Summary
Changes in pHi are key to sperm signaling[3,4,5,6,7,8,9,10,11], but it is not known if SLC9C1 promotes Na+/H+ exchange, how its activity is controlled, and whether it contributes to pHi regulation. The pHi of SLC9C1−/− sperm is not altered[2], and a clear-cut conclusion is compounded by the unexpected observation that cAMP synthesis is impaired in SLC9C1−/− sperm and that the motility defect can be rescued by cAMP12,13 These observations suggest that the prime defect of SLC9C1−/− sperm might be in cAMP—rather than pHi signaling. On a different yet related note, in sea urchin sperm, chemoattractants stimulate a rapid rise of pHi9,14–20, which serves as a switch to activate the pH-sensitive CatSper Ca2+ channel that controls chemotaxis[9]. The molecule underlying this alkalinization is not known. Our results enable future studies of the commonalities and differences of voltage sensing and cAMP modulation between ion channels and a solute carrier and, thereby, gain insight into the evolution of gating mechanisms
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