Abstract 2575: Mechanisms Underlying Activation of Constitutive Acetylcholine-regulated Potassium Channels by Atrial Tachycardia Remodeling
Background: Atrial tachycardia remodeling (ATR) enhances constitutive acetylcholine regulated K+ current (IKAChC), which causes APD shortening and AF promotion. The underlying molecular mechanisms are unknown. Here we examined the role of G-proteins and regulation by classical Ca2+-dependent PKC (cPKC) and novel (nPKC) isoforms.
Methods: Cell-attached single-channel IKACh was recorded with carbachol (10 μM) in the pipette (agonist-activated current, IKAChA) and in its absence (IKAChC) in atrial cells from control (CTL) and ATR (400 bpm × 1 wk) dogs.
Results: ATR increased IKAChC opening frequency (fo) from 2.2±0.2 to 15.3±0.6 Hz (figure⇓). The Gβγ-scavenger M119 inhibited IKAChC similarly for CTL and ATR (by 67±2%, 65±1%), and more than IKAChA (by 27±2%). Combined cPKC/nPKC inhibition with BIM-I enhanced IKAChA (by 14±3%) but suppressed ATR-IKAChC (by 35±5%), suggesting stimulatory effects of some PKC isoforms and inhibitory effects of others. Selective inhibition of cPKC with GÖ-6976 had no effect on IKAChC but enhanced IKAChA, indicating tonic IKAChA suppression by cPKC. Combined cPKC/nPKC stimulation with PMA inhibited IKAChA and CTL-IKAChC (by 25±6%, 29±11%) but enhanced ATR-IKAChC, suggesting inhibitory cPKC effects in CTL but a countervailing stimulatory effect of nPKC in ATR. Selective stimulation of nPKC with PMA in the presence of GÖ-6976 or BAPTA-AM enhanced ATR-IKAChC (by 58±9%, 36±6%) but did not affect IKAChA, confirming a stimulatory effect of nPKC in ATR that is absent in CTL.
Conclusions: Isoform-specific PKC activation underlies ATR-induced IKAChC enhancement, with a shift to nPKC-mediated stimulation predominating over cPKC-induced inhibition.