HCN-related channelopathies.
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.
Baruscotti
Mirko
M
Department of Biomolecular Sciences and Biotechnology, The PaceLab, University of Milano and Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Milano, Italy. mirko.baruscotti@unimi.it
Bottelli
Georgia
G
Milanesi
Raffaella
R
DiFrancesco
Jacopo C
JC
DiFrancesco
Dario
D
D000595:Amino Acid Sequence; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D053447:Channelopathies / Q000503:physiopathology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000502:physiology*; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D006321:Heart / Q000502:physiology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D012849:Sinoatrial Node / Q000502:physiology
D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D020033:Protein Isoforms