Evidence of involvement of GIRK1/GIRK4 in long-term desensitization of cardiac muscarinic K+ channels

The cardiac M-2 muscarinic receptor/G protein/K+ channel system was studied in neonatal rat atrial cells cultured with and without 10 muM carbachol (C Ch) for 24 h. Channel activity in CCh-pretreated cells was substantially re duced as a result of long-term desensitization regardless of whether the ch annel was activated by ACh in cell-attached patches or GTP in inside-out pa tches. Channel activity in CCh-pretreated cells was also low when the recep tor was bypassed and the G protein and channel were directly activated by [ gamma -S] GTP or both the receptor and G protein were bypassed and the chan nel was directly activated by trypsin. Finally, in CCh-pretreated cells, th e whole cell K+ current was low when the channel was activated via the inde pendent adenosine receptor. This suggests that the channel is involved in l ong-term desensitization. However, in CCh-pretreated cells, although the re ceptor was internalized, there was no internalization of the channel. We su ggest that the function of the muscarinic K+ channel declines in long-term desensitization of the cardiac M-2 muscarinic receptor/G protein/K+ channel system.