RT Journal Article
SR Electronic
T1 Evidence for a Novel K<sup>+</sup> Channel Modulated by α<sub>1A</sub>-Adrenoceptors in Cardiac Myocytes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 735
OP 748
DO 10.1124/mol.104.000760
VO 66
IS 3
A1 Choisy, Stéphanie C. M.
A1 Hancox, Jules C.
A1 Arberry, Lesley A.
A1 Reynolds, A. Martyn
A1 Shattock, Michael J.
A1 James, Andrew F.
YR 2004
UL http://molpharm.aspetjournals.org/content/66/3/735.abstract
AB 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 α1-adrenoceptor (α1-AR) agonist] on a sustained outward K+ current in rat ventricular myocytes. Under K+ current-selective conditions at 35°C and whole-cell patch clamp, membrane depolarization elicited transient (It) and steady-state (Iss) outward current components. PE (10 μM) significantly decreased Iss amplitude, without significant effect on It. Preferential modulation of Iss by PE was confirmed by intracellular application of the voltage-gated K+ channel blocker tetraethylammonium, which largely inhibited It without affecting the PE-sensitive current (Iss,PE). Iss,PE had the properties of an outwardly rectifying steady-state K+-selective conductance. Acidification of the external solution or externally applied BaCl2 or quinidine strongly inhibited Iss,PE. However, Iss,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 Iss,PE yielded a large unitary conductance of 78 pS. Iss,PE resulted from PE activation of the α1A-AR subtype, involved a pertussis toxin-insensitive G-protein, and was independent of cytosolic Ca2+. These results collectively demonstrate that α1A-AR activation results in the inhibition of an outwardly rectifying steady-state K+ current with properties distinct from previously characterized cardiac K+ channels.