The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.
The voltage-dependent K+ channels belonging to the ether-à-go-go family (eag, erg, elk) are widely expressed in the mammalian CNS. Their neuronal function, however, is poorly understood. Among the elk clones, elk2 is the most abundantly expressed in the brain. We have characterized the human ELK2 channel (HELK2) expressed in mammalian cell lines. Moreover, we have detected helk2 mRNA and ELK2-like currents in freshly dissociated human astrocytoma cells. HELK2 was inhibited by Cs+ in a voltage-dependent way (Kd was 0.7 mm, at -120 mV). It was not affected by Way 123398 (5 micro m), dofetilide (10 micro m), quinidine (10 micro m), verapamil (20 micro m), haloperidol (2 micro m), astemizole (1 micro m), terfenadine (1 micro m) and hydroxyzine (30 micro m), compounds known to inhibit the biophysically related HERG channel. The crossover of the activation and inactivation curves produced a steady state 'window' current with a peak around -20 mV and considerably broader than it usually is in voltage-dependent channels, including HERG. Similar features were observed in the ELK2 clone from rat, in the same experimental conditions. Thus, ELK2 channels are active within a wide range of membrane potentials, both sub- and suprathreshold. Moreover, the kinetics of channel deactivation and removal of inactivation was about one order of magnitude quicker in HELK2, compared to HERG. Overall, these properties suggest that ELK2 channels are very effective at dampening the neuronal excitability, but less so at producing adaptation of action potential firing frequency. In addition, we suggest experimental ways to recognize HELK2 currents in vivo and raise the issue of the possible function of these channels in astrocytoma.
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy. andrea.becchetti@unimib.it
Andrea
A
Becchetti
Maurizio
M
De Fusco
Olivia
O
Crociani
Alessia
A
Cherubini
Rita
R
Restano-Cassulini
Marzia
M
Lecchi
Alessio
A
Masi
Annarosa
A
Arcangeli
Giorgio
G
Casari
Enzo
E
Wanke
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D027682:Cation Transport Proteins; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014407:Tumor Cells, Cultured
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005904:Glial Fibrillary Acidic Protein; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG