title: A novel α-conotoxin MII-sensitive nicotinic acetylcholine receptor modulates [(3) H]-GABA release in the superficial layers of the mouse superior colliculus.
abstract: Mouse superficial superior colliculus (SuSC) contains dense GABAergic innervation and diverse nicotinic acetylcholine receptor subtypes. Pharmacological and genetic approaches were used to investigate the subunit compositions of nicotinic acetylcholine receptors (nAChR) expressed on mouse SuSC GABAergic terminals. [(125) I]-Epibatidine competition-binding studies revealed that the α3β2* and α6β2* nicotinic subtype-selective peptide α-conotoxin MII-blocked binding to 40 ± 5% of SuSC nAChRs. Acetylcholine-evoked [(3) H]-GABA release from SuSC crude synaptosomal preparations is calcium dependent, blocked by the voltage-sensitive calcium channel blocker, cadmium, and the nAChR antagonist mecamylamine, but is unaffected by muscarinic, glutamatergic, P2X and 5-HT3 receptor antagonists. Approximately 50% of nAChR-mediated SuSC [(3) H]-GABA release is inhibited by α-conotoxin MII. However, the highly α6β2*-subtype-selective α-conotoxin PIA did not affect [(3) H]-GABA release. Nicotinic subunit-null mutant mouse experiments revealed that ACh-stimulated SuSC [(3) H]-GABA release is entirely β2 subunit-dependent. α4 subunit deletion decreased total function by >90%, and eliminated α-conotoxin MII-resistant release. ACh-stimulated SuSC [(3) H]-GABA release was unaffected by β3, α5 or α6 nicotinic subunit deletions. Together, these data suggest that a significant proportion of mouse SuSC nicotinic agonist-evoked GABA-release is mediated by a novel, α-conotoxin MII-sensitive α3α4β2 nAChR. The remaining α-conotoxin MII-resistant, nAChR agonist-evoked SuSC GABA release appears to be mediated via α4β2* subtype nAChRs.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
authors.forename: Tristan D
authors.initials: TD
authors.lastname: McClure-Begley
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wageman
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Allan C
authors.initials: AC
authors.lastname: Collins
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002038:Bungarotoxins / Q000494:pharmacology; D020916:Conotoxins / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013477:Superior Colliculi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D014326:Tropanes / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D020916:Conotoxins; D018691:Excitatory Amino Acid Antagonists; D007456:Iodine Isotopes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011725:Pyridines; D011978:Receptors, Nicotinic; D012702:Serotonin Antagonists; D014326:Tropanes; C098872:alpha-conotoxin MII; D014316:Tritium; D005680:gamma-Aminobutyric Acid; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000255:Adenosine Triphosphate; C082748:epibatidine; D000109:Acetylcholine; C042253:bemesetron