Abstract
Impaired GIRK channel activity in the cardiac atria has been implicated in the development of atrial fibrillation. GIRK channels are essential to the maintenance of the resting membrane potential and inhibitory post-synaptic potentials in the body. In the cardiac atria, GIRK1/4 channels play a role in the down-stroke of the atrial action potential during atrial re polarization. The over-activity of GIRK channels is hence implicated in the shortening of the atrial action potential and the effective refractory period. Both these electrophysiological changes allow for an increased firing rate by the atria and a de-synchrony between the upper and lower chambers of the heart. The resulting irregular heart rate is a hallmark of atrial fibrillation. We show that GIRK1/4 channel activity is enhanced by the novel isoform of PKC, PKCε, and inhibited by the conventional isoform, PKCα. Both PKCε and PKCα also modulate the activity of GIRK1 and GIRK4 subunits, individually. Additionally, we demonstrate that this change in channel activity due to PKC is a result of direct and specific phosphorylation of each channel subunit and its subsequent alteration of channel-PIP2 interactions. Existing therapies for AF are non-specific and are fraught with their own limitations. The mechanistic insight into GIRK1/4 pathological activity is guiding design of therapeutic small-molecule channel inhibitors.
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