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.

A synthetic peptide that prevents cAMP regulation in mammalian hyperpolarization-activated cyclic nucleotide-gated (HCN) channels / A. Saponaro, F. Cantini, A. Porro, A. Bucchi, D. Difrancesco, V. Maione, C. Donadoni, B. Introini, P. Mesirca, M.E. Mangoni, G. Thiel, L. Banci, B. Santoro, A. Moroni. - In: ELIFE. - ISSN 2050-084X. - 7(2018 Jun 20), pp. e35753.1-e35753.22. [10.7554/eLife.35753]

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

A. Saponaro;A. Porro;A. Bucchi;C. Donadoni;B. Introini;A. Moroni
2018

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.
HCN; cAMP; cardiac pacemaker; molecular biophysics; mouse; structural biology
Settore BIO/04 - Fisiologia Vegetale
Settore BIO/09 - Fisiologia
   HCN channel dysfunction in Alzheimer's disease
   FONDAZIONE CARIPLO
   2014-0796

   Noninvasive Manipulation of Gating in Ion Channels
   noMAGIC
   EUROPEAN COMMISSION
   H2020
   695078
20-giu-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/585385
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