The m1 muscarinic acetylcholine receptor transactivates the EGF receptor to modulate ion channel activity.
Intracellular tyrosine kinases link the G protein-coupled m1 muscarinic acetylcholine receptor (mAChR) to multiple cellular responses. However, the mechanisms by which m1 mAChRs stimulate tyrosine kinase activity and the identity of the kinases within particular signaling pathways remain largely unknown. We show that the epidermal growth factor receptor (EGFR), a single transmembrane receptor tyrosine kinase, becomes catalytically active and dimerized through an m1 mAChR-regulated pathway that requires protein kinase C, but is independent of EGF. Finally, we demonstrate that transactivation of the EGFR plays a major role in a pathway linking m1 mAChRs to modulation of the Kv1.2 potassium channel. These results demonstrate a ligand-independent mechanism of EGFR transactivation by m1 mAChRs and reveal a novel role for these growth factor receptors in the regulation of ion channels by G protein-coupled receptors.
Tsai
W
W
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Morielli
A D
AD
Peralta
E G
EG
D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection
D007473:Ion Channels; C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D004815:Epidermal Growth Factor; D002217:Carbachol; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins