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A synthetic peptide that prevents cAMP regulation in mammalian Hyperpolarization-activated Cyclic Nucleotide-regulated (HCN) channels.

Saponaro, Andrea ; Cantini, Francesca ; Porro, Alessandro ; Bucchi, Annalisa ; DiFrancesco, Dario ; Maione, Vincenzo ; Donadoni, Chiara ; Introini, Bianca ; Mesirca, Pietro ; Mangoni, Matteo Elia ; Thiel, Gerhard ; Banci, Lucia ; Santoro, Bina ; Moroni, Anna (2018):
A synthetic peptide that prevents cAMP regulation in mammalian Hyperpolarization-activated Cyclic Nucleotide-regulated (HCN) channels.
In: eLife, 7, pp. pii: e35753. ISSN 2050-084X,
[Article]

Abstract

Binding of TRIP8b to the cyclic nucleotide binding domain (CNBD) of mammalian 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 (TRIP8b) that recapitulates affinity and gating effects of TRIP8b in HCN isoforms (human hHCN1, mHCn2, rbHCN4) and in the cardiac current I in rabbit and mouse sinoatrial node cardiomyocytes. Guided by a NMR-derived structural model that identifies the key molecular interactions between TRIP8b and HCN CNBD, we further designed a cell-penetrating peptide (TAT-TRIP8b) which successfully prevented b-adrenergic activation of mouse I leaving the stimulation of the L-type calcium current (I) unaffected. TRIP8b 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: 2018
Creators: Saponaro, Andrea ; Cantini, Francesca ; Porro, Alessandro ; Bucchi, Annalisa ; DiFrancesco, Dario ; Maione, Vincenzo ; Donadoni, Chiara ; Introini, Bianca ; Mesirca, Pietro ; Mangoni, Matteo Elia ; Thiel, Gerhard ; Banci, Lucia ; Santoro, Bina ; Moroni, Anna
Title: A synthetic peptide that prevents cAMP regulation in mammalian Hyperpolarization-activated Cyclic Nucleotide-regulated (HCN) channels.
Language: English
Abstract:

Binding of TRIP8b to the cyclic nucleotide binding domain (CNBD) of mammalian 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 (TRIP8b) that recapitulates affinity and gating effects of TRIP8b in HCN isoforms (human hHCN1, mHCn2, rbHCN4) and in the cardiac current I in rabbit and mouse sinoatrial node cardiomyocytes. Guided by a NMR-derived structural model that identifies the key molecular interactions between TRIP8b and HCN CNBD, we further designed a cell-penetrating peptide (TAT-TRIP8b) which successfully prevented b-adrenergic activation of mouse I leaving the stimulation of the L-type calcium current (I) unaffected. TRIP8b 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
Journal Volume: 7
Divisions: 10 Department of Biology
10 Department of Biology > Plant Membrane Biophysics
Date Deposited: 26 Jun 2018 08:42
Identification Number: pmid:29923826
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