A Novel Mechanism of Modulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channels by Src Kinase

Zong, Xin; Eckert, Christian; Yuan, Hai‐Xin; Wahl‐Schott, Christian; Abicht, Heike; Fang, Longfou; Li, Rongxia; Mistrík, Pavel; Gerstner, Andrea; Much, Barbara; Baumann, Ludwig; Michalakis, Stylianos; Zeng, Rong; Chen, Zhengjun; Biel, Martin

doi:10.1074/jbc.m506544200

Cited by 89 publications

(101 citation statements)

References 56 publications

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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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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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“…Although it has been reported to increase the activation kinetics and the currents of HCN1 and 2 [43,44] , it decreases the activation kinetics but increases the I f current when it is associated with HCN4 [45] . Other HCN regulatory mechanism have been described, including phosphatidylinositol 4,5-bisphosphate (PIP 2 ) modulation [46] or the direct actions of kinases [47] and phosphatases [48,49] . Loss of function of HCN4 due to mutations or nonspecific pharmacological blockade leads to sick sinus syndrome, which is a general inability of the SAN to impose its sinusal rhythm on the conducting system.…”

Section: Membrane or Voltage Clock Modelmentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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“…B. Kaupp, FZJ-IBI-1 Jülich, Germany), anti-tubulin (1:400; Dianova, Germany). Co-immunoprecipitation was performed as described previously (27). For immunoprecipitation 210 g of olfactory membranes were incubated with 10 g of C-AbmCNGA2 or 10 g of anti-PAK (control antibody; sc-882, Santa Cruz Biotechnologies).…”

Section: Animals-the Generation Of Cngb1mentioning

confidence: 99%

Loss of CNGB1 Protein Leads to Olfactory Dysfunction and Subciliary Cyclic Nucleotide-gated Channel Trapping

Michalakis

Reisert

Geiger

et al. 2006

Journal of Biological Chemistry

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Olfactory receptor neurons (ORNs) employ a cyclic nucleotide-gated (CNG) channel to generate a receptor current in response to an odorant-induced rise in cAMP. This channel contains three types of subunits, the principal CNGA2 subunit and two modulatory subunits (CNGA4 and CNGB1b). Here, we have analyzed the functional relevance of CNGB1 for olfaction by gene targeting in mice. Electro-olfactogram responses of CNGB1-deficient (CNGB1 ؊/؊ ) mice displayed a reduced maximal amplitude and decelerated onset and recovery kinetics compared with wild-type mice. In a behavioral test, CNGB1؊/؊ mice exhibited a profoundly decreased olfactory performance. Electrophysiological recordings revealed that ORNs of CNGB1 ؊/؊ mice weakly expressed a CNG current with decreased cAMP sensitivity, very rapid flicker-gating behavior and no fast modulation by Ca 2؉ -calmodulin. Co-immunoprecipitation confirmed the presence of a CNGA2/CNGA4 channel in the olfactory epithelium of CNGB1 ؊/؊ mice. This CNGA2/CNGA4 channel was targeted to the plasma membrane of olfactory knobs, but failed to be trafficked into olfactory cilia. Interestingly, we observed a similar trafficking defect in mice deficient for the CNGA4 subunit. In conclusion, these results demonstrate that CNGB1 has a dual function in vivo. First, it endows the olfactory CNG channel with a variety of biophysical properties tailored to the specific requirements of olfactory transduction. Second, together with the CNGA4 subunit, CNGB1 is needed for ciliary targeting of the olfactory CNG channel. Cyclic nucleotide-gated (CNG)3 channels are molecular switches converting receptor-mediated increases in cytosolic concentrations of cAMP or cGMP into an influx of cations. The channels play a key role in visual and olfactory transductions. The CNG channel involved in olfaction is expressed at high density in the sensory cilia of olfactory receptor neurons (ORNs) where it is activated by an odorant-induced rise of cAMP. When open, the channel conducts mainly Ca 2ϩ and Na ϩ (1, 2). The subsequent rise in internal Ca 2ϩ

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A Novel Mechanism of Modulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channels by Src Kinase

Cited by 89 publications

References 56 publications

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

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

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

Loss of CNGB1 Protein Leads to Olfactory Dysfunction and Subciliary Cyclic Nucleotide-gated Channel Trapping

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