A novel role for HERG K+ channels: spike-frequency adaptation.
1. The regular firing of a Hodgkin-Huxley neurone endowed with fast Na+ and delayed K+ channels can be converted into adapting firing by appending HERG (human eag-related gene) channels. 2. The computer model predictions were verified by studying the firing properties of F-11 DRG neurone x neuroblastoma hybrid cells induced to differentiate by long-term exposure to retinoic acid. These cells, which express HERG currents (IHERG), show clear spike-frequency adaptation of their firing when current clamped with long depolarizations. 3. In agreement with the prediction, the selective blocking of IHERG by class III antiarrhythmic drugs always led to the disappearance of the spike-frequency adaptation, and the conversion of adapting firing to regular firing. 4. It is proposed that, in addition to their role in the repolarization of the heart action potential, HERG channels may sustain a process of spike-frequency adaptation, and hence contribute to the control of burst duration in a way that is similar to that of the K+ currents, IAHP, IC and IM. In addition to the known cardiac arrhythmia syndrome (LQT2), genetic mutations or an altered HERG expression could lead to continuous hyperexcitable states sustained by the inability of nerve or endocrine cells to accommodate to repetitive stimuli. This might help in clarifying the pathogenesis of still undefined idiopathic familial epilepsies.
Chiesa
N
N
Department of General Physiology and Biochemistry, University of Milano, Italy.
Rosati
B
B
Arcangeli
A
A
Olivotto
M
M
Wanke
E
E
D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism; D027682:Cation Transport Proteins; D002999:Clone Cells; D003198:Computer Simulation; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; C000606915:Kcnh2 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG