Inactivation in HCN Channels Results from Reclosure of the Activation Gate

Shin, Ki Soon; Maertens, Chantal; Proenza, Catherine; Rothberg, Brad S.; Yellen, Gary

doi:10.1016/s0896-6273(04)00083-2

Cited by 106 publications

(173 citation statements)

References 20 publications

(2 reference statements)

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“…These findings most likely reflect a destabilization of the open state, causing local perturbations in conformation that could allow channels to close during depolarizations. This finding is similar to a proposed mechanism of current decay during long periods of activation proposed in spHCN channels (Shin et al, 2004) and in Kv4.2 (Dougherty et al, 2008), and is consistent with the finding that multiple pathways of current decay exist in other Kv1 channels, as was shown in Kv1.3 (Marom and Levitan, 1994). Though it represents a different conclusion, this result also appears to be consistent with observations of a shorter mean open time in single-channel analysis of homotetramers of Kv1.1 V408A as well as Kv1.1-Kv1.2 heterotetramers possessing the same mutation (D'Adamo et al, 1999).…”

Section: Discussionsupporting

confidence: 90%

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

Peters

Werry²,

Gill³

et al. 2011

J. Neurosci.

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In Kv1.1, single point mutants found below the channel activation gate at residue V408 are associated with human episodic ataxia type-1, and impair channel function by accelerating decay of outward current during periods of membrane depolarization and channel opening. This decay is usually attributed to C-type inactivation, but here we provide evidence that this is not the case. Using voltage-clamp fluorimetry in Xenopus oocytes, and single-channel patch clamp in mouse ltk؊ cells, of the homologous Shaker channel (with the equivalent mutation V478A), we have determined that the mutation may cause current decay through a local effect at the activation gate, by destabilizing channel opening. We demonstrate that the effect of the mutant is similar to that of trapped 4-aminopyridine in antagonizing channel opening, as the mutation and 10 mM 4-AP had similar, nonadditive effects on fluorescence recorded from the voltagesensitive S4 helix. We propose a model where the Kv1.1 activation gate fails to enter a stabilized open conformation, from which the channel would normally C-type inactivate. Instead, the lower pore lining helix is able to enter an activated-not-open conformation during depolarization. These results provide an understanding of the molecular etiology underlying episodic ataxia type-1 due to V408A, as well as biophysical insights into the links between the potassium channel activation gate, the voltage sensor and the selectivity filter.

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Section: Discussionsupporting

confidence: 90%

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

Peters

Werry²,

Gill³

et al. 2011

J. Neurosci.

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“…These arguments for distinct manifestations of channel inhibition are very similar to those proposed to account for different forms of activation induced by cAMP in two HCN channels (Shin et al, 2004), although in that previous model, an inactivated state was introduced to account for the somewhat anomalous behavior of a sea urchin HCN channel. In addition, an analogous situation obtains in the related cyclic nucleotide-gated (CNG) channels (Fodor et al, 1997).…”

Section: Allosteric Modulation Of Halothane-mediated Hcn Channel Inhisupporting

confidence: 63%

“…Previous mutagenesis studies demonstrated that the C terminus of HCN2 imparts substantially more basal inhibition to its core channel domains than does the C terminus of HCN1, accounting for its more hyperpolarized initial V 1/2 (Wainger et al, 2001;Wang et al, 2001); binding of cAMP to the C terminus acts to relieve basal inhibition, producing a more prominent depolarizing shift in V 1/2 of HCN2 channels. Based on a simplified model of HCN channel gating, adapted from Shin et al (2004), we suggest that differences in C-terminally mediated basal inhibition can lead primarily to a shift in V 1/2 or amplitude inhibition despite a common underlying inhibitory mechanism, i.e., stabilization of channel closed state.…”

Section: Allosteric Modulation Of Halothane-mediated Hcn Channel Inhimentioning

confidence: 99%

“…For the illustration, the voltage-dependent step (i.e., C R 3 C A ) was simulated assuming a steepness of e-fold per 6.5 mV and a midpoint of activation of Ϫ98 mV, as determined experimentally for HCN2; results are qualitatively identical using measured values from HCN1 (e-fold per 7 mV and a midpoint of activation of Ϫ80 mV). The simplified model [adapted from Shin et al (2004)] and the arbitrarily defined equilibrium constants are provided below the plots. Simulated currents were obtained with QuB freeware (http://www.qub.buffalo.edu/), and steady-state values were used to generate activation curves and determine relative current amplitudes.…”

Section: Allosteric Modulation Of Halothane-mediated Hcn Channel Inhimentioning

confidence: 99%

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HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Chen

Sirois²,

Lei³

et al. 2005

Journal of Neuroscience

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General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA A receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (I h ) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal I h and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of I h involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V 1/2 and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics.

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“…The current conducted by the HCN channels, I h , is rapidly and transiently modified by cAMP-mediated gating (Wang et al, 2002;Shin et al, 2004), altered channel phosphorylation (Zong et al, 2005;Poolos et al, 2006) and additional, undefined processes (Van Welie et al, 2004;Fan et al, 2005). Whereas these modulations are transient and reversible, transcriptional changes of HCN channel expression may last for months, alter neuronal firing patterns and contribute to a hyperexcitable hippocampal network (Chen et al, 2001;Brewster et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

Richichi

Brewster

Bender

et al. 2008

Neurobiology of Disease

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Epilepsy may result from abnormal function of ion channels, such as those caused by genetic mutations. Recently, pathological alterations of the expression or localization of normal channels have been implicated in epilepsy generation, and termed 'acquired channelopathies'. Altered expression levels of the HCN channels--that conduct the hyperpolarization-activated current, I h --have been demonstrated in hippocampus of patients with severe temporal lobe epilepsy as well as in animal models of temporal lobe and absence epilepsies. Here we probe the mechanisms for the altered expression of HCN channels which is provoked by seizures. In organotypic hippocampal slice cultures, seizure-like events selectively reduced HCN type 1 channel expression and increased HCN2 mRNA levels, as occurs in vivo. The mechanisms for HCN1 reduction involved Ca 2+ -permeable AMPA receptors-mediated Ca 2+ influx, and subsequent activation of Ca 2+ /calmodulin-dependent protein kinase II. In contrast, upregulation of HCN2 expression was independent of these processes. The data demonstrate an orchestrated program for seizure-evoked transcriptional channelopathy involving the HCN channels, that may contribute to certain epilepsies.

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Inactivation in HCN Channels Results from Reclosure of the Activation Gate

Cited by 106 publications

References 20 publications

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore

HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels

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