Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Voltage-dependent opening of HCN channels: Facilitation or inhibition by the phytoestrogen, genistein, is determined by the activation status of the cyclic nucleotide gating ring.
Rozario AO
,
Turbendian HK
,
Fogle KJ
,
Olivier NB
,
Tibbs GR
.
???displayArticle.abstract???
Investigation of the mechanistic bases and physiological importance of cAMP regulation of HCN channels has exploited an arginine to glutamate mutation in the nucleotide-binding fold, an approach critically dependent on the mutation selectively lowering the channel's nucleotide affinity. In apparent conflict with this, in intact Xenopus oocytes, HCN and HCN-RE channels exhibit qualitatively and quantitatively distinct responses to the tyrosine kinase inhibitor, genistein -- the estrogenic isoflavonoid strongly depolarizes the activation mid-point of HCN1-R538E, but not HCN1 channels (+9.8 mV + or - 0.9 versus +2.2 mV + or - 0.6) and hyperpolarizes gating of HCN2 (-4.8 mV + or - 1.0) but depolarizes gating of HCN2-R591E (+13.2 mV + or - 2.1). However, excised patch recording, X-ray crystallography and modeling reveal that this is not due to either a fundamental effect of the mutation on channel gating per se or of genistein acting as a mutation-sensitive partial agonist at the cAMP site. Rather, we find that genistein equivalently moves both HCN and HCN-RE channels closer to the open state (rendering the channels inherently easier to open but at a cost of decreasing the coupling energy of cAMP) and that the anomaly reflects a balance of these energetic effects with the isoform-specific inhibition of activation by the nucleotide gating ring and relief of this by endogenous cAMP. These findings have specific implications with regard to findings based on HCN-RE channels and kinase antagonists and general implications with respect to interpretation of drug effects in mutant channel backgrounds.
Altomare,
Direct inhibition of the pacemaker (If) current in rabbit sinoatrial node cells by genistein.
2006, Pubmed
Altomare,
Direct inhibition of the pacemaker (If) current in rabbit sinoatrial node cells by genistein.
2006,
Pubmed
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001,
Pubmed
Arinsburg,
Constitutively active Src tyrosine kinase changes gating of HCN4 channels through direct binding to the channel proteins.
2006,
Pubmed
Barbuti,
Action of internal pronase on the f-channel kinetics in the rabbit SA node.
1999,
Pubmed
Barbuti,
Localization of pacemaker channels in lipid rafts regulates channel kinetics.
2004,
Pubmed
Bruening-Wright,
Slow conformational changes of the voltage sensor during the mode shift in hyperpolarization-activated cyclic-nucleotide-gated channels.
2007,
Pubmed
,
Xenbase
Bruening-Wright,
Kinetic relationship between the voltage sensor and the activation gate in spHCN channels.
2007,
Pubmed
,
Xenbase
Brünger,
Crystallography & NMR system: A new software suite for macromolecular structure determination.
1998,
Pubmed
Chen,
Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
2001,
Pubmed
,
Xenbase
Chen,
Voltage sensor movement and cAMP binding allosterically regulate an inherently voltage-independent closed-open transition in HCN channels.
2007,
Pubmed
,
Xenbase
Craven,
Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels.
2004,
Pubmed
,
Xenbase
Craven,
C-terminal movement during gating in cyclic nucleotide-modulated channels.
2008,
Pubmed
,
Xenbase
Craven,
CNG and HCN channels: two peas, one pod.
2006,
Pubmed
DiFrancesco,
Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node.
1999,
Pubmed
Elinder,
Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels.
2006,
Pubmed
,
Xenbase
Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed
Flynn,
Structure and rearrangements in the carboxy-terminal region of SpIH channels.
2007,
Pubmed
,
Xenbase
Fogle,
HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2.
2007,
Pubmed
,
Xenbase
Harzheim,
Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP.
2008,
Pubmed
Hua,
Functional interactions between A' helices in the C-linker of open CNG channels.
2005,
Pubmed
,
Xenbase
Huang,
Novel mechanism for suppression of hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by receptor-like tyrosine phosphatase-alpha.
2008,
Pubmed
Jones,
Improved methods for building protein models in electron density maps and the location of errors in these models.
1991,
Pubmed
Kramer,
Modulation of cyclic-nucleotide-gated channels and regulation of vertebrate phototransduction.
2001,
Pubmed
Lyashchenko,
Ion binding in the open HCN pacemaker channel pore: fast mechanisms to shape "slow" channels.
2008,
Pubmed
,
Xenbase
Lyashchenko,
Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core.
2007,
Pubmed
,
Xenbase
Molokanova,
Noncatalytic inhibition of cyclic nucleotide-gated channels by tyrosine kinase induced by genistein.
1999,
Pubmed
,
Xenbase
Molokanova,
Subunit contributions to phosphorylation-dependent modulation of bovine rod cyclic nucleotide-gated channels.
2003,
Pubmed
,
Xenbase
Molokanova,
Interactions of cyclic nucleotide-gated channel subunits and protein tyrosine kinase probed with genistein.
2000,
Pubmed
,
Xenbase
Molokanova,
Activity-dependent modulation of rod photoreceptor cyclic nucleotide-gated channels mediated by phosphorylation of a specific tyrosine residue.
1999,
Pubmed
,
Xenbase
Molokanova,
Mechanism of inhibition of cyclic nucleotide-gated channel by protein tyrosine kinase probed with genistein.
2001,
Pubmed
,
Xenbase
Murshudov,
Refinement of macromolecular structures by the maximum-likelihood method.
1997,
Pubmed
Männikkö,
Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.
2005,
Pubmed
,
Xenbase
Otwinowski,
Processing of X-ray diffraction data collected in oscillation mode.
1997,
Pubmed
Pan,
Cortisone dissociates the Shaker family K+ channels from their beta subunits.
2008,
Pubmed
,
Xenbase
Perrakis,
ARP/wARP and molecular replacement.
2001,
Pubmed
Pian,
Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2.
2006,
Pubmed
,
Xenbase
Pian,
Modulation of cyclic nucleotide-regulated HCN channels by PIP(2) and receptors coupled to phospholipase C.
2007,
Pubmed
,
Xenbase
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Shibata,
Inhibition by genistein of the hyperpolarization-activated cation current in porcine sino-atrial node cells.
1999,
Pubmed
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Tibbs,
A state-independent interaction between ligand and a conserved arginine residue in cyclic nucleotide-gated channels reveals a functional polarity of the cyclic nucleotide binding site.
1998,
Pubmed
,
Xenbase
Ulens,
Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry.
2003,
Pubmed
,
Xenbase
Vemana,
Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels.
2008,
Pubmed
,
Xenbase
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wang,
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
2002,
Pubmed
,
Xenbase
Wang,
Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions.
2001,
Pubmed
,
Xenbase
Wu,
Tyrosine kinase inhibition reduces i(f) in rabbit sinoatrial node myocytes.
1997,
Pubmed
Yu,
Tyrosine kinase inhibition differentially regulates heterologously expressed HCN channels.
2004,
Pubmed
,
Xenbase
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
Zhou,
Pathway and endpoint free energy calculations for cyclic nucleotide binding to HCN channels.
2008,
Pubmed
Zhou,
A conserved tripeptide in CNG and HCN channels regulates ligand gating by controlling C-terminal oligomerization.
2004,
Pubmed
,
Xenbase
Zhou,
Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy.
2007,
Pubmed
,
Xenbase
Zolles,
Pacemaking by HCN channels requires interaction with phosphoinositides.
2006,
Pubmed
,
Xenbase
Zong,
A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase.
2005,
Pubmed