Inwardly rectifying potassium channels of the Kir2 subfamiliy are regulated by Gi/o-coupled (Wischmeyer & Karschin, 1996), as well as Gq/11-coupled receptors (Firth & Jones, 2001). So far, it is still under debate whether these receptors selectively target to different members of the Kir2 subfamily.

In order to investigate receptor induced inactivation cRNA of Kir2.1–2.4 together with acetylcholine M1, serotonin 5-HT2C, bradykinin B1 and B2 and histamine H1 receptors, respectively, was injected into Xenopus oocytes. Activation of the M1 receptor reduced the amplitude of Kir2.3 current by 38±5% (10 mM muscarine, n=5). In contrast, all other Kir2 subfamiliy members were not affected by the activation of coexpressed M1 receptors. The same was true for all other Gq/11-coupled receptors tested. None of them reduced Kir2 currents significantly. Further, we tried to find the structural basis of receptor-mediated inhibition of Kir2.3. In contrast to all other members of the Kir2 subfamily, Kir2.3 harbours a stretch of glycine residues within the extracellular loop between transmembrane region M1 and the pore region. However, mutating three of these glycine residues into alanines does not influence receptor-induced inhibition of Kir2.3.

Our results suggest that Kir2.3, but not Kir2.1, Kir2.2 and Kir2.4, is selectively inhibited via the muscarinic M1 receptor.