G protein-activated (GIRK) current in rat ventricular myocytes is masked by constitutive inward rectifier current (I K1 )

Abstract

Inwardly-rectifying K + channel subunits are not homogenously expressed in different cardiac tissues. In ventricular myocytes (VM) the background current-voltage relation is dominated by I K1 , carried by channels composed of Kir2.x subunits, which is less important in atrial myocytes (AM). On the other hand in AM a large G protein gated current carried by Kir3.1/3.4 complexes can be activated by stimulation of muscarinic M 2 receptors (I K(ACh) ), which is assumed to be marginal in VM. Recent evidence suggests that total current carried by cardiac inward-rectifiers (I K(ATP) , I K(ACh) , I K1 ) in both, AM and VM is limited, due to K + accumulation/depletion. This lead us to hypothesize that in conventional whole celI recordings I K(ACh) in VM is underestimated as a consequence of constitutive I K1 . In that case a reduction in density of I K1 should be paralleled by an increase in density of I K(ACh) . Three different experimental strategies have been used to test for this hypothesis: (i) Adenovirus-driven expression of a dominant-negative mutant of Kir2.1, one of the subunits supposed to form I K1 channels, in VM caused a reduction in I K1 -density by about 80 %. In those cells I K(ACh) was increased about 4 fold. (ii) A comparable increase in I K(ACh) was observed upon reduction of I K1 caused by adenovirus-mediated RNA interference.(iii) Ba 2+ in a concentration of 2 μM blocks I K1 in VM by about 60 % without affecting atrial I K(ACh) . The reduction in I K1 by 2 μM Ba 2+ is paralleled by a reversible increase in I K(ACh) by about 100%. These data demonstrate that the increase in K + conductance underlying ventricular I K(ACh) is largely underestimated, suggesting that it might be of greater physiological relevance than previously thought. Copyright © 2008 S. Karger AG.