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Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel

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  • Philipp A. M. Schmidpeter

    (Weill Cornell Medicine, Department of Anesthesiology)

  • Jan Rheinberger

    (Weill Cornell Medicine, Department of Anesthesiology
    University of Groningen)

  • Crina M. Nimigean

    (Weill Cornell Medicine, Department of Anesthesiology
    Weill Cornell Medicine, Department of Physiology and Biophysics)

Abstract

SthK, a cyclic nucleotide-modulated ion channel from Spirochaeta thermophila, activates slowly upon cAMP increase. This is reminiscent of the slow, cAMP-induced activation reported for the hyperpolarization-activated and cyclic nucleotide-gated channel HCN2 in the family of so-called pacemaker channels. Here, we investigate slow cAMP-induced activation in purified SthK channels using stopped-flow assays, mutagenesis, enzymatic catalysis and inhibition assays revealing that the cis/trans conformation of a conserved proline in the cyclic nucleotide-binding domain determines the activation kinetics of SthK. We propose that SthK exists in two forms: trans Pro300 SthK with high ligand binding affinity and fast activation, and cis Pro300 SthK with low affinity and slow activation. Following channel activation, the cis/trans equilibrium, catalyzed by prolyl isomerases, is shifted towards trans, while steady-state channel activity is unaffected. Our results reveal prolyl isomerization as a regulatory mechanism for SthK, and potentially eukaryotic HCN channels. This mechanism could contribute to electrical rhythmicity in cells.

Suggested Citation

  • Philipp A. M. Schmidpeter & Jan Rheinberger & Crina M. Nimigean, 2020. "Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20104-4
    DOI: 10.1038/s41467-020-20104-4
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    Cited by:

    1. Xiaolong Gao & Philipp A. M. Schmidpeter & Vladimir Berka & Ryan J. Durham & Chen Fan & Vasanthi Jayaraman & Crina M. Nimigean, 2022. "Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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