M3 muscarinic receptor activation of a delayed rectifier potassium current in canine atrial myocytes.
Growing body of evidence indicates that the functional responses of cells to muscarinic acetylcholine receptors (mAChRs) are mediated by multiple receptor subtypes. It is commonly thought that the M2 receptor is the only functional mAChR subtype in the heart and little data regarding the potential roles of other subtypes in cardiac tissues has been reported. In the present study, we provide functional evidence for the presence and physiological function of an M3 receptor in canine atrial myocytes. Using whole-cell patch-clamp techniques, we consistently found that pilocarpine, an mAChR agonist, induced a K+ current similar to but distinct from the classical delayed rectifier K+ current. Same observations were obtained when choline or tetramethylammonium (TMA) was applied to the bath. The currents were abolished by 1 microM atropine. Antagonists selective to M1 (pirenzepine, 100 nM), M2 (methoctramine 100 nM), or M4 (tropicamide 200 nM) receptors failed to alter the currents. Conversely, three different M3-selective inhibitors, p-F-HHSiD (20-200 nM), 4-DAMP methiodide (2-10 nM) and 4-DAMP mustard (4-20 nM), all produced concentration-dependent suppression of the currents. A cDNA fragment representing the M3 receptor was isolated from dog atrial RNA and the mRNA level of this construct was 0.7 +/- 0.1 pg/microg total RNA, as quantified by the competitive RT-PCR methods. Our data strongly suggested that an M3 receptor exists and is coupled to a K+ channel in the heart.
Shi
H
H
Research Center, Montreal Heart Institute, Quebec, Canada.
Wang
H
H
Wang
Z
Z
D000818:Animals; D004285:Dogs; D006321:Heart / Q000502:physiology*; D008564:Membrane Potentials; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000502:physiology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D010880:Piperidines; D015221:Potassium Channels; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D013757:Tetraethylammonium Compounds; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium