A role for protein kinase A and protein kinase M zeta in muscarinic acetylcholine receptor-initiated persistent synaptic enhancement in rat hippocampus in vivo.
Antagonists at presynaptic muscarinic autoreceptors increase endogenous acetylcholine (ACh) release and enhance cognition but little is known regarding their actions on plasticity at glutamatergic synapses. Here the mechanisms of the persistent enhancement of hippocampal excitatory transmission induced by the M2/M4 muscarinic ACh receptor antagonist methoctramine were investigated in vivo. The persistent facilitatory effect of i.c.v. methoctramine in the CA1 region of urethane-anesthetized rats was mimicked by gallamine, an M2 receptor antagonist, supporting a role for this receptor subtype. Neither the N-methyl-D-aspartate (NMDA) receptor antagonists D-(-)-2-amino phosphonopentanoic acid (d-AP5) and memantine, nor the metabotropic glutamate receptor subtype 1a antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) significantly affected the methoctramine-induced persistent synaptic enhancement, indicating a lack of requirement for these glutamate receptors. The selective kinase inhibitors Rp-adenosine-3', 5'-cyclic monophosphorothioate (Rp-cAMPS) and the myrostylated pseudosubstrate peptide, Myr-Ser-Ile-Tyr-Arg-Arg-Gly-Ala-Arg-Arg-Trp-Arg-Lys-Leu-OH (ZIP), were used to investigate the roles of protein kinase A (PKA) and the atypical protein kinase C, protein kinase Mzeta (PKM zeta), respectively. Remarkably, pretreatment with either agent prevented the induction of the persistent synaptic enhancement by methoctramine and post-methoctramine treatment with Rp-cAMPS transiently reversed the enhancement. These findings are strong evidence that antagonism of M2 muscarinic ACh receptors in vivo induces an NMDA receptor-independent persistent synaptic enhancement that requires activation of both PKA and PKM zeta.
Department of Pharmacology and Therapeutics, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
J
J
Hayes
S
S
Li
R
R
Anwyl
M J
MJ
Rowan
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D003627:Data Interpretation, Statistical; D003959:Diamines / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000502:physiology; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology
D001565:Benzoates; D003959:Diamines; D018691:Excitatory Amino Acid Antagonists; D010276:Parasympatholytics; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D013873:Thionucleotides; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; C054938:methoctramine; D005998:Glycine