title: GABAB receptor transduction mechanisms, and cross-talk between protein kinases A and C, in GABAergic terminals synapsing onto neurons of the rat nucleus basalis of Meynert.
abstract: The transduction mechanisms underlying presynaptic GABAB receptor-mediated inhibition of transmitter release have been characterized for a variety of synapses in the central nervous system (CNS). These studies have suggested a range of transduction mechanisms, including a role for second messengers such as protein kinases A (PKA) and C (PKC). In the present study, we have examined the intracellular signalling pathways underlying baclofen-induced inhibition of GABA release from terminals synapsing onto rat basalis of Meynert neurons using patch-clamp recordings. Baclofen, a selective GABAB receptor agonist, reversibly decreased both evoked and spontaneous, miniature, GABAergic inhibitory postsynaptic currents (eIPSCs and mIPSCs, respectively). Such baclofen actions were completely abolished by CGP55845A, a selective GABAB receptor antagonist, and by staurosporine, a non-selective PKA and PKC inhibitor. The mIPSC frequency was still decreased by baclofen even in the presence of 4 AP, a K+ channel blocker, and Cd2+, a voltage-dependent calcium channel blocker. Pharmacological activation or inhibition of PKC activity affected basal GABA release and mildly affected the response to baclofen. Inhibition of the cAMP/PKA cascade also affected basal GABA release and, in a subset of neurons, occluded the effects of baclofen, suggesting that the GABAB receptor-mediated inhibitory action on GABA release was mediated via decreases in PKA activity. In addition, PKA inhibition occluded the effects of PKC modulation on both basal GABA release and on the response to baclofen. Our results characterize the transduction pathway of baclofen at these nucleus basalis of Maynert (nBM) synapses and show, for the first time, some cross-talk between the cAMP/PKA and PKC pathways in mammalian presynaptic nerve terminals.
authors.affiliation: Cellular and System Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
authors.forename: Hisahiko
authors.initials: H
authors.lastname: Kubota
authors.forename: Shutaro
authors.initials: S
authors.lastname: Katsurabayashi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Moorhouse
authors.forename: Nobuya
authors.initials: N
authors.lastname: Murakami
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Koga
authors.forename: Norio
authors.initials: N
authors.lastname: Akaike
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D020532:Basal Nucleus of Meynert / Q000166:cytology / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D015221:Potassium Channels; D018080:Receptors, GABA-B; C017759:9-(tetrahydro-2-furyl)-adenine; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D001418:Baclofen; D000225:Adenine