TU Darmstadt / ULB / TUprints

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

Saponaro, Andrea ; Cantini, Francesca ; Porro, Alessandro ; Bucchi, Annalisa ; DiFrancesco, Dario ; Maione, Vincenzo ; Donadoni, Chiara ; Introini, Bianca ; Mesirca, Pietro ; Mangoni, Matteo E. ; Thiel, Gerhard ; Banci, Lucia ; Santoro, Bina ; Moroni, Anna (2022):
A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. (Publisher's Version)
In: eLife, 2018, eLife Sciences Publications, ISSN 2050-084X,
DOI: 10.26083/tuprints-00013339,
[Article]

[img]
Preview
Text
elife-35753-v2.pdf
Available under: CC BY 4.0 International - Creative Commons, Attribution.

Download (3MB) | Preview
Item Type: Article
Origin: Secondary publication
Status: Publisher's Version
Title: A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
Language: English
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.

Journal or Publication Title: eLife
Volume of the journal: 2018
Publisher: eLife Sciences Publications
Collation: 22 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 580 Pflanzen (Botanik)
600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin, Gesundheit
Divisions: 10 Department of Biology > Plant Membrane Biophysics
Date Deposited: 01 Mar 2022 08:53
Last Modified: 10 Mar 2022 09:23
DOI: 10.26083/tuprints-00013339
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-133393
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/13339
PPN:
Export:
Actions (login required)
View Item View Item