G protein-activated inward-rectifying K⁺ (GIRK) channels are expressed in neuronal, cardiac, and endocrine tissue, where they participate in postsynaptic inhibition, vagally induced bradycardia, and regulation of hormone secretion. Canonical activation occurs by binding of ßg-subunits upon G_i/o protein coupled receptor stimulation. Additionally, we have demonstrated activation solely of Kir3.4 homomers by binding of intracellular Na⁺ ions^[1]. GIRK channels are tetramers comprised of various combinations of Kir3.x isoforms, while a cardiac GIRK channel is supposed to be composed of two Kir3.1 and two Kir3.4 subunits. Nevertheless, Kir3.1 transcripts in atrial myocytes are > 10 fold more abundant than Kir3.4 transcripts. There is still little known about the impact of subunit expression ratios on current properties. It has been demonstrated that Kir3.1 subunits do not form functional channels, whereas formation of Kir3.4 homomeric channels can be induced in atrial myocytes by overexpressing this subunit. Macroscopic Kir3.4 channel currents can be distinguished from Kir3.1/Kir3.4 by significantly weaker inward rectification and receptor-independent activation by intracellular Na⁺. We hypothesized that the excess of Kir3.1 prevents formation of homomeric Kir3.4 channels. Adenovirus-driven RNA-interference targeting Kir3.1 resulted in a reduction of GIRK current density by about 80%. The remaining current had properties of heteromeric channels namely strong inward rectification and lack of Na⁺-sensitivity, suggesting that reduction of Kir3.1 does not favor formation of homomeric Kir3.4 complexes. However, siRNA induced reduction in Kir3.1 mRNA was paralleled by a reduction in Kir3.4 mRNA, suggesting a co-regulation of Kir3.1 and Kir3.4 on the transcriptional level.

^[1]Mintert E et al. J Phys. 2007: 585(Pt 1):3–13