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PreprintCited by 0Ion channel regulation and functionCardiac electrophysiology and arrhythmiasIon Transport and Channel Regulation

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.

LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction

Open access
Peters, Colin H, Singh, Rohit K, Langley, Avery A, Nichols, William G, Ferris, Hannah R, Jeffrey, Danielle A, Proenza, Catherine, Bankston, John R·2024·eLife
DOI 10.7554/elife.92411.2

Preprint — published as 10.7554/elife.92411.3

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Abstract

Abstract Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation. We show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating. And we demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we showed that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. And we demonstrate that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of 5 residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.

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Crossref · 10.7554/elife.92411.2

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Metadata

Authors
Peters, C. H., Singh, R. K., Langley, A. A., Nichols, W. G., Ferris, H. R., Jeffrey, D. A., Proenza, C., & Bankston, J. R.
Affiliations
University of Colorado Anschutz (US)
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-04-10
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.92411.2
OpenAlex
W4394692059
Cited by
0
References
39
Type
posted content
Language
en
Open access
Licence
Locations
eLife (acceptedVersion, cc-by)
Funders
  • National Institute of General Medical Sciences (R35GM137912, R01GM140004)
  • National Heart, Lung, and Blood Institute (R01HL088427)
  • American Heart Association (830889, 19POST34380777)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
HCN4, HCN2, cyclic nucleotide-gated channels, channel gating, intramolecular signal transduction, isoform specificity, protein-protein interaction, C-linker, S4-S5 linker, hyperpolarization-activated channels

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