ERKI/II regulation by the muscarinic acetylcholine receptors in neurons.
Muscarinic acetylcholine receptors (mAChRs) are known to be involved in learning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has revealed a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK in neurons. Using the MAPK kinase (MEK)-specific inhibitor PD98059, we first demonstrate a necessary role for active ERKI/II in long-term potentiation in vivo. Using phospho-specific antibodies that recognize the activated form of ERKI/II, we find that the level of ERKI/II activation in brain is regulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activation of ERKI/II, without effect on the related kinase SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal protein kinase) in primary cortical cultures. ERKI/II activation is Src-dependent and partially phosphoinositide-3 kinase- and Ca(2+)-dependent but is PKC-independent. M1-M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal transduction pathway similar to that operating in neurons. The nature of the signal transduction suggests that ERKI/II can serve as a convergence site for mAChR activation and other neurotransmitter receptors.
Rosenblum
K
K
Division of Neurophysiology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom. krosenb@nimr.mrc.ac.uk
Futter
M
M
Jones
M
M
Hulme
E C
EC
Bliss
T V
TV
D000818:Animals; D001921:Brain / Q000201:enzymology; D019556:COS Cells; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
D007527:Isoenzymes; D020033:Protein Isoforms; D011976:Receptors, Muscarinic; D002217:Carbachol; D019061:src-Family Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases