title: Differential actions of PKA and PKC in the regulation of glutamate release by group III mGluRs in the entorhinal cortex.
abstract: In a previous study we showed that activation of a presynaptically located metabotropic glutamate receptor (mGluR) with pharmacological properties of mGluR4a causes a facilitation of glutamate release in layer V of the rat entorhinal cortex (EC) in vitro. In the present study we have begun to investigate the intracellular coupling linking the receptor to transmitter release. We recorded spontaneous alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated excitatory postsynaptic currents (EPSCs) in the whole cell configuration of the patch-clamp technique, from visually identified neurons in layer V. Bath application of the protein kinase A (PKA) activator, forskolin, resulted in a marked facilitation of EPSC frequency, similar to that seen with the mGluR4a specific agonist, ACPT-1. Preincubation of slices with the PKA inhibitor H-89 abolished the effect of ACPT-1, as did preincubation with the adenylate cyclase inhibitor, SQ22536. Activation of protein kinase C (PKC) using phorbol 12 myristate 13-acetate (PMA) did not affect sEPSC frequency; however, it did abolish the facilitatory effect of ACPT-1 on glutamate release. A robust enhancement of EPSC frequency was seen in response to bath application of the specific PKC inhibitor, GF 109203X. Both H-89 and the group III mGluR antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) abolished the effects of GF 109203X. These data suggest that in layer V of the EC, presynaptic group III mGluRs facilitate release via a positive coupling to adenylate cyclase and subsequent activation of PKA. We have also demonstrated that the PKC system tonically depresses transmitter release onto layer V cells of the EC and that an interaction between mGluR4a, PKA, and PKC may exist at these synapses.
authors.affiliation: Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: D I
authors.initials: DI
authors.lastname: Evans
authors.forename: R S
authors.initials: RS
authors.lastname: Jones
authors.forename: G
authors.initials: G
authors.lastname: Woodhall
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003517:Cyclopentanes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013449:Sulfonamides; D014233:Tricarboxylic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C409063:1-aminocyclopentane-1,2,4-tricarboxylic acid; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; D014233:Tricarboxylic Acids; C104331:cyclopropyl-4-phosphonophenylglycine; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000225:Adenine; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C047983:1,9-dideoxyforskolin; D005998:Glycine