Rhythmic Control Of Atrial GIRK Channel Function By PKC

Abstract

G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in the regulation of beat to beat variability of the heart (Wickman et al., 1998), yet the mechanisms that control this variability are not well understood. We hypothesized that different kinases known to regulate GIRK channel function might generate rhythmic changes in GIRK channel sensitivity to G protein stimulation in a “tug of war” manner with the PP1 and PP2A phosphatases associated with GIRK channels (Nikolov and Ivanova-Nikolova, 2004). To test this hypothesis we recorded the activity of single GIRK channels excised from the membrane of atrial myocytes in the presence of purified Gβγ and PKC. As previously reported, PKC abolished the activity of the canonical 35-pS GIRK1/4 channels. In contrast, PKC induced rhythmic activity of the small conductance GIRK (scGIRK) channels, residing in the atrial membrane. This rhythmic activity of scGIRK channels arises from constant concentration of Gβγ, PKC and ATP and greatly expands the dynamic repertoire of the signaling system. PKC has pivotal role in signal transduction as modulator of the amplitude of protein function. Our data reveal that in addition to its canonical role in signaling pathways, PKC has the ability to assemble molecular clocks out of common membrane components expanding the dynamic nature of cellular signaling.