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J Physiol
2007 Aug 15;583Pt 1:37-56. doi: 10.1113/jphysiol.2007.136465.
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Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core.
Lyashchenko AK
,
Redd KJ
,
Yang J
,
Tibbs GR
.
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Activation of native IH pacemaker channels and channels formed on heterologous expression of some isoforms of their pore forming HCN (hyperpolarization-activated, cyclic nucleotide-regulated) subunits is inhibited by the intravenous general anaesthetic propofol (2,6-diisopropylphenol). Here, we show that inhibition of homomeric HCN1 channels is mediated through anaesthetic association with the membrane embedded channel core, a domain that is highly conserved between this isoform and the relatively insensitive HCN2 and 4 subunits. Decoupling of HCN channel gating from cAMP and internal protons reveals that changes in these second messengers are neither necessary nor sufficient to account for propofol's actions. Modelling of the equilibrium and kinetic behaviour of HCN1 channels in the absence and presence of anaesthetic reveals that (1) gating is best described by models wherein closed and open states communicate via a voltage-independent reaction with no significant equilibrium occupancy of a deactivated open state at non-permissive voltages, and (2) propofol modifies gating by preferentially associating with closed-resting and closed-activated states but a low affinity interaction with the activated open state shapes the effect of the drug under physiological conditions. Our findings illuminate the mechanism of HCN channel gating and provide a framework that will facilitate development of propofol derivates that have altered pharmacological properties and therapeutic potentials.
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001, Pubmed
Altomare,
Integrated allosteric model of voltage gating of HCN channels.
2001,
Pubmed
Azene,
Pore-to-gate coupling of HCN channels revealed by a pore variant that contributes to gating but not permeation.
2005,
Pubmed
,
Xenbase
Azene,
Molecular basis of the effect of potassium on heterologously expressed pacemaker (HCN) channels.
2003,
Pubmed
,
Xenbase
Azene,
Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers.
2005,
Pubmed
,
Xenbase
Biel,
Cardiac HCN channels: structure, function, and modulation.
2002,
Pubmed
Cacheaux,
Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol.
2005,
Pubmed
,
Xenbase
Chen,
Voltage sensor movement and cAMP binding allosterically regulate an inherently voltage-independent closed-open transition in HCN channels.
2007,
Pubmed
,
Xenbase
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,
Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.
2005,
Pubmed
,
Xenbase
Chen,
HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents.
2005,
Pubmed
Craven,
Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels.
2004,
Pubmed
,
Xenbase
Craven,
CNG and HCN channels: two peas, one pod.
2006,
Pubmed
Dekker,
Cooperative gating between single HCN pacemaker channels.
2006,
Pubmed
DiFrancesco,
Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node.
1994,
Pubmed
DiFrancesco,
Characterization of single pacemaker channels in cardiac sino-atrial node cells.
,
Pubmed
Elinder,
Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels.
2006,
Pubmed
,
Xenbase
Fogle,
HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2.
2007,
Pubmed
,
Xenbase
Funahashi,
Propofol suppresses a hyperpolarization-activated inward current in rat hippocampal CA1 neurons.
2001,
Pubmed
Gravante,
Interaction of the pacemaker channel HCN1 with filamin A.
2004,
Pubmed
Heinemann,
Nonstationary noise analysis and application to patch clamp recordings.
1992,
Pubmed
Higuchi,
Suppression of the hyperpolarization-activated inward current contributes to the inhibitory actions of propofol on rat CA1 and CA3 pyramidal neurons.
2003,
Pubmed
Männikkö,
Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.
2005,
Pubmed
,
Xenbase
McCormick,
Sleep and arousal: thalamocortical mechanisms.
1997,
Pubmed
Munsch,
Modulation of the hyperpolarization-activated cation current of rat thalamic relay neurones by intracellular pH.
1999,
Pubmed
Pian,
Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2.
2006,
Pubmed
,
Xenbase
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Santoro,
The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels.
1999,
Pubmed
Shin,
Inactivation in HCN channels results from reclosure of the activation gate: desensitization to voltage.
2004,
Pubmed
Sirois,
Multiple ionic mechanisms mediate inhibition of rat motoneurones by inhalation anaesthetics.
1998,
Pubmed
Steffan,
Error estimates for results of nonstationary noise analysis derived with linear least squares methods.
1997,
Pubmed
,
Xenbase
Steriade,
Thalamocortical oscillations in the sleeping and aroused brain.
1993,
Pubmed
Ulens,
Regulation of hyperpolarization-activated HCN channels by cAMP through a gating switch in binding domain symmetry.
2003,
Pubmed
,
Xenbase
Veintemilla,
Mechanisms of propofol action on ion currents in the myelinated axon of Xenopus laevis.
1992,
Pubmed
,
Xenbase
Wang,
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
2002,
Pubmed
,
Xenbase
Ying,
Propofol block of I(h) contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons.
2006,
Pubmed
Zolles,
Pacemaking by HCN channels requires interaction with phosphoinositides.
2006,
Pubmed
,
Xenbase
Zong,
A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2.
2001,
Pubmed
