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Molecular and Cellular pH Regulation

Thomas Berger

Thomas Berger

Orcid - Pubmed

Cells need to maintain a stable pH (i.e. proton concentration) for proper functioning. In addition, the function of several proteins is regulated by changes in intra- or extracellular pH. Cells control the intracellular pH by buffers, enzymes, exchangers, pumps, and ion channels. We investigate cellular and molecular mechanisms that control pH regulation in cells. Our focus is on voltage-gated ion channels that conduct protons and thereby regulate the intracellular pH as a function of the membrane potential. Voltage-gated proton channels can be found in a variety of cell types, including immune cells, epithelial cells, and sperm. However, the precise physiological role of proton channels is only poorly understood in most cell types.

Two voltage-gated proton channels have been identified in eukaryotes: the depolarization-activated proton channel Hv1 and the hyperpolarization-activated proton channel HCNL1. Interestingly, in both channels, protons take an unusual permeation pathway through the voltage-sensing domain (VSD, see Figure). HCNL1 has a non-conducting pore domain (PD), while Hv1 does not contain a PD at all.

Two key research questions are currently addressed:

1. Molecular mechanism of proton permeation. How do HCNL1 and Hv1 channels achieve high proton selectivity?

2. Physiological role of proton channels in sperm.

We use molecular biological, electrophysiological, and fluorescence-optical methods to address these questions.

Interested? for further information!

Key Publications

Wobig L, Wolfenstetter T, Fechner S, Bönigk W, Körschen HG, Jikeli JF, Trötschel C, Feederle R, Kaupp UB, Seifert R, Berger TK (2020) A family of hyperpolarization-activated channels selective for protons.  Proc. Natl. Acad. Sci. U.S.A. 117:13783-91.

Rennhack A, Grahn E, Kaupp UB, Berger TK (2017) Photocontrol of the Hv1 Proton Channel. ACS Chem. Biol. 12:2952-7.

Berger TK, Fußhöller DM, Goodwin N, Bönigk W, Müller A, Dokani Khesroshahi N, Brenker C, Wachten D, Krause E, Kaupp UB, Strünker T (2017) Post-translational cleavage of Hv1 in human sperm tunes pH- and voltage-dependent gating. J. Physiol. 595:1533-46.

Mony L, Berger TK, Isacoff EY (2015) A specialized molecular motion opens the Hv1 voltage-gated proton channel. Nat. Struct. Mol. Biol. 22:283-90.

Berger TK, Isacoff EY (2015) Fluorescent labeling for patch-clamp fluorometry (PCF) measurements of real-time protein motion in ion channels. Methods Mol. Biol. 1266:93-106.

Berger TK, Isacoff EY (2011) The pore of the voltage-gated proton channel. Neuron 72:991-1000.