Evidence of involvement of GIRK1/GIRK4 in long-term desensitization of cardiac muscarinic K+ channels.
The cardiac M2 muscarinic receptor/G protein/K+ channel system was studied in neonatal rat atrial cells cultured with and without 10 microM carbachol (CCh) for 24 h. Channel activity in CCh-pretreated cells was substantially reduced as a result of long-term desensitization regardless of whether the channel was activated by ACh in cell-attached patches or GTP in inside-out patches. Channel activity in CCh-pretreated cells was also low when the receptor 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 channel was directly activated by trypsin. Finally, in CCh-pretreated cells, the whole cell K+ current was low when the channel was activated via the independent adenosine receptor. This suggests that the channel is involved in long-term desensitization. However, in CCh-pretreated cells, although the receptor was internalized, there was no internalization of the channel. We suggest that the function of the muscarinic K+ channel declines in long-term desensitization of the cardiac M2 muscarinic receptor/G protein/K+ channel system.
Shui
Z
Z
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
Yamanushi
T T
TT
Boyett
M R
MR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D002217:Carbachol; D014357:Trypsin; D019204:GTP-Binding Proteins; D000109:Acetylcholine; D011188:Potassium