ERG K+ channel blockade enhances firing and epinephrine secretion in rat chromaffin cells: the missing link to LQT2-related sudden death?
The ether-a-go-go-related genes (erg) are expressed in tissues other than heart and brain, in which human erg (HERG) K+ channels are known to regulate the repolarization of heart action potentials and neuronal spike-frequency accommodation. We provide evidence that erg1 transcripts and ERG proteins are present in rat chromaffin cells in which we could isolate a K+ current that was biophysically and pharmacologically similar to the ERG current. Firing frequency and catecholamine release were analyzed at the single-cell level by means of perforated patch-clamp and carbon fiber electrochemical detection. It was found that the blocking of ERG, KATP, and KCa channels led to hyperexcitability and an increase in catecholamine release. Combined immunocytochemical experiments with antibodies directed against phenylethanolamine N-methyltransferase and ERG channels suggested expression of these channels in epinephrine- but not in norepinephrine-containing cells. It is concluded that, in addition to being crucial in regulating the QT period in the heart, ERG channels play a role in modulating epinephrine, a fundamental neurotransmitter shaping cardiac function. This finding suggests that the sudden death phenotype associated with LQT2 syndrome mutations may be the result of an emotionally triggered increase in epinephrine in a long-QT running heart.
Gullo
Francesca
F
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, I-20126 Milano, Italy.
Ales
Eva
E
Rosati
Barbara
B
Lecchi
Marzia
M
Masi
Alessio
A
Guasti
Leonardo
L
Cano-Abad
María F
MF
Arcangeli
Annarosa
A
Lopez
Manuela G
MG
Wanke
Enzo
E
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004837:Epinephrine / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels; D015870:Gene Expression; D006632:Histamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D013424:Sulfanilamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001562:Benzimidazoles; D002118:Calcium; D002395:Catecholamines; D000072237:ERG1 Potassium Channel; D004837:Epinephrine; D051638:Ether-A-Go-Go Potassium Channels; D006632:Histamine; D009538:Nicotine; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013424:Sulfanilamides; C000606913:KCNH2 protein, human; C073190:WAY 123398; D000096926:Benzenesulfonamides