The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands

It is well known that activation of the cloned kappa-opioid receptor by nan omolar concentrations of U50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1 - pyrrolidinyl]cyclohexyl-benzeneacetamide), a selective kappa-opioid recep tor agonist, leads to the opening of GIRK1 channels. In this study, we demo nstrate that the cloned kappa-opioid receptor functionally couples to GIRK1 /GIRK2 channels (G-protein-coupled inwardly rectifying K+ channels), mimick ing the probable heteromultimeric state of neuronal GIRK channels. We also show that micromolar concentrations of U50488H reduce GIRK1/GIRK2 current t hrough direct GIRK1/GIRK2 channel block in a voltage-independent manner (IC S50 = 70.28 +/- 3.68 mu M). Similarly, it was found that propoxyphene, meth adone, and naloxone also can block GIRK1/GIRK2 current. In contrast, elevat ed concentrations of morphine (up to 1 mM) did not cause channel block. The related inwardly rectifying K+ channel, IRK1, was not affected by elevated concentrations of these drugs. We conclude that nanomolar concentrations o f opioid receptor ligands activate GIRK1/GIRK2 channels through a receptor- mediated pathway, while micromolar concentrations of some opioid receptor l igands inhibit GIRK1/GIRK2 channels by direct channel block. (C) 1999 Elsev ier Science B.V. All rights reserved.