The “Funny” Pacemaker Current

Barbuti, Andrea; Bucchi, Annalisa; Baruscotti, Mirko; DiFrancesco, Dario

doi:10.1002/9780470561416.ch3

Cited by 2 publications

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References 213 publications

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“…the α-subunits), and that disturbances of the pacemaker process can also derive from alterations of auxiliary subunits or interfering proteins (such as for example MiRP1 49,50 or caveolin-3 47,51,52 ) or other proteins such as KCR1 and SAP97. 53 Screening of these proteins in arrhythmia patients can thus provide useful insight into new potentially causative mutations.…”

Section: Screening Of Defective Hcn4 Auxiliary Subunits -Mirp1mentioning

confidence: 99%

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HCN4, Sinus Bradycardia and Atrial Fibrillation

DiFrancesco¹

2015

Arrhythmia &Amp; Electrophysiology Review

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Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/ hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation.Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.

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Section: Screening Of Defective Hcn4 Auxiliary Subunits -Mirp1mentioning

confidence: 99%

“…53 Clearly, in this latter case other channels may also undergo modifications since auxiliary subunits often regulate multiple targets. HCN4 mutations found so far are all loss-of-function, and it will be interesting to see if gain-of-function mutations also occur.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

HCN4, Sinus Bradycardia and Atrial Fibrillation

DiFrancesco¹

2015

Arrhythmia &Amp; Electrophysiology Review

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HCN-related channelopathies

Baruscotti

Bottelli

Milanesi

et al. 2010

Pflugers Arch - Eur J Physiol

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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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The “Funny” Pacemaker Current

Cited by 2 publications

References 213 publications

HCN4, Sinus Bradycardia and Atrial Fibrillation

HCN4, Sinus Bradycardia and Atrial Fibrillation

HCN-related channelopathies

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