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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.
In: eLife, 2018, 2018
doi: 10.26083/tuprints-00013339
Article, Secondary publication, Publisher's Version

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.

Item Type: Article
Erschienen: 2022
Creators: 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
Type of entry: Secondary publication
Title: A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
Language: English
Date: 2022
Year of primary publication: 2018
Publisher: eLife Sciences Publications
Journal or Publication Title: eLife
Volume of the journal: 2018
Collation: 22 Seiten
DOI: 10.26083/tuprints-00013339
URL / URN: https://tuprints.ulb.tu-darmstadt.de/13339
Corresponding Links:
Origin: Secondary publication
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.

Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-133393
Classification DDC: 500 Science and mathematics > 580 Plants (botany)
600 Technology, medicine, applied sciences > 610 Medicine and health
Divisions: 10 Department of Biology
10 Department of Biology > Plant Membrane Biophyscis (20.12.23 renamed in Biology of Algae and Protozoa)
Date Deposited: 01 Mar 2022 08:53
Last Modified: 02 Mar 2022 07:07
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