Abstract
Activation of extracellular signal-regulated kinases (ERK) is crucial for many neural functions, including learning, memory, and synaptic plasticity. As muscarinic acetylcholine receptors (mAChR) modulate many of the same higher brain functions as ERK, we examined mAChR-mediated ERK activation in mouse hippocampal slices. The cholinergic agonist carbachol caused an atropine-sensitive ERK activation in the dendrites and somata CA1 pyramidal neurons. To determine the responsible mAChR subtype, we combined pharmacologic and genetic approaches. Pretreatment with M1 antagonists inhibited ERK activation. Furthermore, mAChR-induced ERK activation was absent in slices from M1 knockout mice. ERK activation was normal in slices derived from other mAChR subtype knockouts (M2, M3, and M4), although these other subtypes are expressed in many of the same neurons. Thus, we demonstrate divergent functions for the different mAChR subtypes. We conclude that M1 is responsible for mAChR-mediated ERK activation, providing a mechanism by which M1 may modulate learning and memory.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Atropine / pharmacology
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Carbachol / pharmacology
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Cell Nucleus / metabolism
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Cell Nucleus / ultrastructure
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Cholinergic Agonists / pharmacology
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Dendrites / metabolism
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Dendrites / ultrastructure
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Dose-Response Relationship, Drug
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / enzymology*
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MAP Kinase Kinase 1
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Male
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Mecamylamine / pharmacology
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism*
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Muscarinic Antagonists / pharmacology
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Nicotinic Antagonists / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pyramidal Cells / cytology
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Pyramidal Cells / drug effects
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Pyramidal Cells / enzymology*
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Receptor, Muscarinic M1
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Receptors, Muscarinic / deficiency*
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Receptors, Muscarinic / drug effects
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Receptors, Muscarinic / genetics
Substances
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Cholinergic Agonists
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Muscarinic Antagonists
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Nicotinic Antagonists
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Receptor, Muscarinic M1
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Receptors, Muscarinic
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Mecamylamine
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Atropine
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Carbachol
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases