RECEPTOR KINASE-DEPENDENT DESENSITIZATION OF THE MUSCARINIC K+ CURRENT IN RAT ATRIAL CELLS

1. Activity of rat atrial muscarinic K+ channels has been measured in five configurations of the patch clamp technique. 2. In configurations in which the normal intracellular solution was lost, the slow phase o f desensitization (a slow decline of channel activity during an exposu re to ACh) was much reduced (or absent) and deactivation (on wash-off of ACh) was slowed as compared with desensitization and deactivation i n configurations in which normal intracellular solution was retained. This suggests that soluble intracellular regulators are involved in th ese processes. 3. When a G protein-coupled receptor kinase (GRK2) was applied to the cytoplasmic surface of conventional outside-out patches in the presence of ATP, the slow phase of desensitization was restore d. In the absence of ATP, GRK2 failed to restore the slow phase. 4. It is concluded that (i) G protein-coupled receptor kinase dependent pho sphorylation of the muscarinic receptor is responsible for the slow ph ase of desensitization and (ii) a soluble factor (such as a GTPase act ivating protein or 'GAP') is responsible for normal rapid deactivation .