Format

Send to

Choose Destination
Elife. 2018 Jun 20;7. pii: e35753. doi: 10.7554/eLife.35753.

A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

Author information

1
Department of Biosciences, University of Milan, Milan, Italy.
2
Department of Chemistry, University of Florence, Florence, Italy.
3
Magnetic Resonance Center, University of Florence, Florence, Italy.
4
Interuniversity Consortium for Magnetic Resonance of Metalloproteins, Sesto Fiorentino, Italy.
5
Institut de Génomique Fonctionnelle, CNRS, INSERM F-34094, Université de Montpellier, Montpellier, France.
6
Laboratory of Excellence Ion Channels Science and Therapeutics, Valbonne, France.
7
Department of Biology, TU-Darmstadt, Darmstadt, Germany.
8
Institute of Neurosciences, Consiglio Nazionale delle Ricerche, Florence, Italy.
9
Department of Neuroscience, Columbia University, New York, United States.
10
Institute of Biophysics, Consiglio Nazionale delle Ricerche, Milan, Italy.

Abstract

Binding of TRIP8b to the cyclic nucleotide binding domain (CNBD) of mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels prevents their regulation by cAMP. Since TRIP8b is expressed exclusively in the brain, we envisage that it can be used for orthogonal control of HCN channels beyond the central nervous system. To this end, we have identified by rational design a 40-aa long peptide (TRIP8bnano) that recapitulates affinity and gating effects of TRIP8b in HCN isoforms (hHCN1, mHCN2, rbHCN4) and in the cardiac current If in rabbit and mouse sinoatrial node cardiomyocytes. Guided by an NMR-derived structural model that identifies the key molecular interactions between TRIP8bnano and the HCN CNBD, we further designed a cell-penetrating peptide (TAT-TRIP8bnano) which successfully prevented β-adrenergic activation of mouse If leaving the stimulation of the L-type calcium current (ICaL) unaffected. TRIP8bnano represents a novel approach to selectively control HCN activation, which yields the promise of a more targeted pharmacology compared to pore blockers.

KEYWORDS:

HCN; cAMP; cardiac pacemaker; molecular biophysics; mouse; structural biology

Comment in

PMID:
29923826
PMCID:
PMC6023613
DOI:
10.7554/eLife.35753
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

AS, FC, AP, AB, DD, VM, CD, BI, PM, MM, GT, LB, BS, AM No competing interests declared

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center