title: Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes.
abstract: Activation of nicotinic acetylcholine receptors (nAChRs) can elicit neurotransmitter release from presynaptic nerve terminals. Mechanisms contributing to cell-and-terminal specific regulation of nAChR-mediated neurotransmitter exocytosis are not fully understood. The experiments discussed here examine how activation of GABAB auto- and hetero-receptors suppress nAChR-mediated release of [(3)H]-GABA and [(3)H]-dopamine ((3)H-DA) from mouse striatal synaptosomes. Activation of presynaptic GABAB receptors with (R)-baclofen decreased both [(3)H]-GABA and [(3)H]-DA release evoked by potassium depolarization. However, when nAChRs were activated with ACh to evoke neurotransmitter release, (R)-baclofen had no effect on [(3)H]-DA release, but potently inhibited ACh-evoked [(3)H]-GABA release. Inhibition of nAChR-evoked [(3)H]-GABA release by (R)-baclofen was time sensitive and the effect was lost after prolonged exposure to the GABAB agonist. The early inhibitory effect of GABAB activation on ACh-evoked [(3)H]-GABA release was partially attenuated by antagonists of the phosphatase, calcineurin. Furthermore, antagonists of protein kinase C (PKC) prevented the time-dependent loss of the inhibitory (R)-baclofen effect on [(3)H]-GABA release. These results suggest that α4β2*-nAChRs present on GABAergic nerve terminals in the striatum are subject to functional regulation by GABAB autoreceptors that is apparently cell-type specific, since it is absent from DAergic striatal nerve terminals. In addition, the functional modulation of α4β2*-type nAChRs on striatal GABAergic nerve terminals by GABAB autoreceptor activation is time-sensitive and appears to involve opposing actions of calcineurin and PKC.
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States of America; Department of Integrative Physiology, University of Colorado, Boulder, CO, United States of America; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, United States of America.
authors: Tristan D
authors: TD
authors: McClure-Begley
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States of America.
authors: Sharon R
authors: SR
authors: Grady
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States of America; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, United States of America.
authors: Michael J
authors: MJ
authors: Marks
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States of America.
authors: Allan C
authors: AC
authors: Collins
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, United States of America; Department of Integrative Physiology, University of Colorado, Boulder, CO, United States of America. Electronic address: Jerry.Stitzel@colorado.edu.
authors: Jerry A
authors: JA
authors: Stitzel
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000378:metabolism; D001418:Baclofen / Q000494:pharmacology*; D065095:Calcineurin Inhibitors; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011189:Potassium Chloride / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011722:Pyrethrins / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D017660:Autoreceptors; D065095:Calcineurin Inhibitors; D058786:GABA-B Receptor Agonists; D011722:Pyrethrins; D018080:Receptors, GABA-B; D011978:Receptors, Nicotinic; C017160:cypermethrin; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D011493:Protein Kinase C; D001418:Baclofen; D004298:Dopamine
keywords: Calcineurin; GABA(B) receptor; Neurotransmitter release; Nicotinic receptor; Protein kinase C