Evidence for a novel K(+) channel modulated by alpha(1A)-adrenoceptors in cardiac myocytes.
Accumulating evidence suggests that steady-state K(+) currents modulate excitability and action potential duration, particularly in cardiac cell types with relatively abbreviated action potential plateau phases. Despite representing potential drug targets, at present these currents and their modulation are comparatively poorly characterized. Therefore, we investigated the effects of phenylephrine [PE; an alpha(1)-adrenoceptor (alpha(1)-AR) agonist] on a sustained outward K(+) current in rat ventricular myocytes. Under K(+) current-selective conditions at 35 degrees C and whole-cell patch clamp, membrane depolarization elicited transient (I(t)) and steady-state (I(ss)) outward current components. PE (10 microM) significantly decreased I(ss) amplitude, without significant effect on I(t). Preferential modulation of I(ss) by PE was confirmed by intracellular application of the voltage-gated K(+) channel blocker tetraethylammonium, which largely inhibited I(t) without affecting the PE-sensitive current (I(ss,PE)). I(ss,PE) had the properties of an outwardly rectifying steady-state K(+)-selective conductance. Acidification of the external solution or externally applied BaCl(2) or quinidine strongly inhibited I(ss,PE). However, I(ss,PE) was not abolished by anandamide, ruthenium red, or zinc, inhibitors of TASK acid-sensitive background K(+) channels. Furthermore, the PE-sensitive current was partially inhibited by external administration of high concentrations of tetraethylammonium and 4-aminopyridine, which are voltage-gated K(+) channel-blockers. Power spectrum analysis of I(ss,PE) yielded a large unitary conductance of 78 pS. I(ss,PE) resulted from PE activation of the alpha(1A)-AR subtype, involved a pertussis toxin-insensitive G-protein, and was independent of cytosolic Ca(2+). These results collectively demonstrate that alpha(1A)-AR activation results in the inhibition of an outwardly rectifying steady-state K(+) current with properties distinct from previously characterized cardiac K(+) channels.
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
Stéphanie C M
SC
Choisy
Jules C
JC
Hancox
Lesley A
LA
Arberry
A Martyn
AM
Reynolds
Michael J
MJ
Shattock
Andrew F
AF
James
D000138:Acidosis; D000818:Animals; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins; D037342:Pertussis Toxin / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D000081033:Potassium Channels, Sodium-Activated; D024683:Potassium Channels, Tandem Pore Domain; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors
C547715:Adra1a protein, rat; C480493:Kcnt2 potassium channel, rat; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D024683:Potassium Channels, Tandem Pore Domain; D018340:Receptors, Adrenergic, alpha-1; C420132:potassium channel subfamily K member 3; D010656:Phenylephrine; D019789:Tetraethylammonium; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D011802:Quinidine