The solute carrier SLC9C1 is a Na+ /H+ -exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding

Nature Communications
F WindlerU Benjamin Kaupp

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.

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Citations

Mar 12, 2019·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Yasushi Okamura, Yoshifumi Okochi
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Sep 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Nima RafatiLeif Andersson
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Feb 6, 2020·Frontiers in Cell and Developmental Biology·Julio C ChávezTakuya Nishigaki
Nov 21, 2020·Nature Reviews. Urology·Huafeng WangJean-Ju Chung
Aug 28, 2020·Molecular and Cellular Endocrinology·Eduardo R S Roldan, Maria Eugenia Teves
Aug 28, 2021·Frontiers in Pharmacology·Vojtech DvorakGiulio Superti-Furga
Nov 6, 2021·Development·Chieh-Hsiang Tan, Kerry Kornfeld

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Methods Mentioned

BETA
affinity purification
PCR
MDS

Software Mentioned

CorelDrawX6
Biokine
Photo
CatSper
PaintX6

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