ERKI/II regulation by the muscarinic acetylcholine receptors in neurons

Muscarinic acetylcholine receptors (mAChRs) are known to be involved in lea rning and memory, but the molecular basis of their involvement is not well understood. The availability of new and specific biochemical tools has reve aled a crucial role for the mitogen-activated protein kinase (MAPK) family in learning and memory. Here, we examine the link between mAChRs and MAPK i n 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 fo rm of ERKI/II, we find that the level of ERKI/II activation in brain is reg ulated by mAChRs. Carbachol, a muscarinic agonist, induces prolonged activa tion of ERKI/II, without effect on the related kinase SAPK/JNK (stress-acti vated protein kinase/c-Jun N-terminal protein kinase) in primary cortical c ultures. ERKI/II activation is Src-dependent and partially phosphoinositide -3 kinase- and Ca2+-dependent but is PKC-independent. M1-M4 mAChR subtypes expressed in COS-7 cells can all induce ERKI/II activation using a signal t ransduction 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.