HCN-related channelopathies

Department of Biomolecular Sciences and Biotechnology, The PaceLab, University of Milano and Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Milano, Italy.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 03/2010; 460(2):405-15. DOI: 10.1007/s00424-010-0810-8
Source: PubMed


HCN channels are the molecular subunits of native funny (f-) channels of cardiac pacemaker cells and neurons. Although funny channels were first functionally described in cardiac cells in the late 1970s, cloning of HCN channels, of which four subunits are known today (HCN1-4), had to wait some 20 years to be accomplished, which delayed the investigation of HCN-related channelopathies. In cardiac pacemaker cells, the main function of f-channels is to contribute substantially to the generation of spontaneous activity of pacemaker cells and control of heart rate. Given this role in cardiac rhythm, it is natural to expect that defective f-channels (or their molecular correlates HCN4 channels) might be responsible for inheritable forms of cardiac arrhythmogenic diseases. Indeed, the recent search for HCN4-related inheritable arrhythmias has resulted in the finding of four different mutations of the hHcn4 gene, which have been reported to be associated with bradycardia and/or more complex arrhythmic conditions. In neurons, HCN channels display a variety of functions including the regulation of excitability, dendritic integration, plasticity, motor learning, generation of repetitive firing, and others. Defective HCN channels may therefore in principle also contribute to pathological conditions in the nervous system. While full evidence for neuronal HCN channelopathies is not yet available, several indications point to a link between temporal lobe and absence epilepsies and altered distribution of HCN1/HCN2 isoforms. Here we briefly review the current knowledge of HCN-related channelopathies in the heart and the brain.

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Available from: Jacopo C. DiFrancesco
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    • "Since its discovery and until a decade ago, the vast majority of studies on the If current were carried out in single SAN cells isolated from lower mammals, typically rabbit; recent evidence in humans has confirmed previous conclusions on If properties and function. More specifically: (1) the presence of If and HCN1 and HCN4 isoforms has been verified also in human SAN cells (Verkerk et al., 2007a,b; Chandler et al., 2009); (2) genetically determined alterations of the If channel have been associated with mild or severe forms of arrhythmias in humans (Baruscotti et al., 2010b); (3) an If specific blocker, ivabradine, acts as pure heart rate slowing drug and is currently used in the therapy of chronic stable angina and heart failure (DiFrancesco and Camm, 2004). "
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    ABSTRACT: In the adult animal the sinoatrial node (SAN) rhythmically generates a depolarizing wave that propagates to the rest of the heart. However, the SAN is more than a simple clock; it is a clock that adjusts its pace according to the metabolic requirements of the organism. The Hyperpolarization-activated Cyclic Nucleotide-gated channels (HCN1-4) are the structural component of the funny (If) channels; in the SAN the If current is the main driving electrical force of the diastolic depolarization and the HCN4 is the most abundant isoform. The generation of HCN KO mouse models has advanced the understanding of the role of these channels in cardiac excitability. The HCN4 KO models that were first developed allowed either global or cardiac-specific constitutive ablation of HCN4 channels, and resulted in embryonic lethality. A further progress was made with the development of three separate inducible HCN4 KO models; in one model KO was induced globally in the entire organism, in a second, ablation occurred only in HCN4-expressing cells, and finally in a third model KO was confined to cardiac cells. Unexpectedly, the three models yielded different results; similarities and differences among these models will be presented and discussed. The functional effects of HCN2 and HCN3 knockout models and transgenic HCN4 mouse models will also be discussed. In conclusion, HCN KO/transgenic models have allowed to evaluate the functional role of the If currents in intact animals as well as in single SAN cells isolated from the same animals. This opportunity is therefore unique since it allows to 1) verify the contribution of specific HCN isoforms to cardiac activity in intact animals, and 2) to compare these results to those obtained in single cell experiments. These combined studies were not possible prior to the development of KO models. Finally, these models represent critical tools to improve our understanding of the molecular basis of some inheritable arrhythmic human pathologies.
    Preview · Article · Jul 2012 · Frontiers in Physiology
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    • "The Ih current was originally described as the inward cation current activated at hyperpolarized membrane potentials which substantially contributes to the spontaneous pacemaker activity of the heart sinoatrial cells. Indeed, attempts to ameliorate cardiac rhythm disorders have established HCN channels as promising drug targets [1], [2]. However, recent studies have shown that HCN channels are associated not only with cardiac dysfunction, but also with neurological disorders such as neuropathic pain and epilepsy [2], [3]. "
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    ABSTRACT: HCN channels are becoming pharmacological targets mainly in cardiac diseases. But apart from their well-known role in heart pacemaking, these channels are widely expressed in the nervous system where they contribute to the neuron firing pattern. Consequently, abolishing Ih current might have detrimental consequences in a big repertoire of behavioral traits. Several studies in mammals have identified the Ih current as an important determinant of the firing activity of dopaminergic neurons, and recent evidences link alterations in this current to various dopamine-related disorders. We used the model organism Drosophila melanogaster to investigate how lack of Ih current affects dopamine levels and the behavioral consequences in the sleep:activity pattern. Unlike mammals, in Drosophila there is only one gene encoding HCN channels. We generated a deficiency of the DmIh core gene region and measured, by HPLC, levels of dopamine. Our data demonstrate daily variations of dopamine in wild-type fly heads. Lack of Ih current dramatically alters dopamine pattern, but different mechanisms seem to operate during light and dark conditions. Behaviorally, DmIh mutant flies display alterations in the rest:activity pattern, and altered circadian rhythms. Our data strongly suggest that Ih current is necessary to prevent dopamine overproduction at dark, while light input allows cycling of dopamine in an Ih current dependent manner. Moreover, lack of Ih current results in behavioral defects that are consistent with altered dopamine levels.
    Full-text · Article · May 2012 · PLoS ONE
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    • "Mammalian HCN channels exhibit two distinct patterns in the S4 segment (Fig. 3B) — one is the presence of a particularly large number of basic residues (2 Lys and 7 Arg residues) [11] [33] [34] and another is a hydrophilic Ser residue that is located in the middle of S4 segment, breaking the regular pattern of a positively charged residue in every third position [31] [34]. The last four Arg residues are believed to correspond to the four Arg residues responsible for gating charge movements in the Shaker and KvAP K V channels [34]. "
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    ABSTRACT: Electrical signaling in animals ensures the rapid and accurate transmission of information, often carried by voltage-gated Na(+), Ca(2+) and K(+) channels that are activated by membrane depolarization. In heart and neurons, a distinct type of ion channel called the hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channel is activated by membrane hyperpolarization. Recent genomic studies have revealed that animal-type voltage-gated Na(+) channels (Liebeskind BJ, et al. 2011. Proc Natl Acad Sci U S A. 108:9154) had evolved in choanoflagellates, one of the unicellular relatives of animals. To date, HCN channels have been considered to be animal-specific. Here, we demonstrate the presence of an HCN channel homolog (SroHCN) in the choanoflagellate protist Salpingoeca rosetta. SroHCN contains highly conserved functional domains and sequence motifs that are correlated with the unique biophysical activities of HCN channels. These findings provide novel genomic insights into the evolution of complex electrical signaling before the emergence of multicellular animals.
    Full-text · Article · Feb 2012 · Genomics
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