A Novel α-Conotoxin Mii-Sensitive Nicotinic Acetylcholine Receptor Modulates [ 3H]-Gaba Release In The Superficial Layers Of The Mouse Superior Colliculus

Department

neurobiology

Document Type

Article

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. [ 125I]-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 [ 3H]-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 [ 3H]-GABA release is inhibited by α-conotoxin MII. However, the highly α6β2*-subtype-selective α-conotoxin PIA did not affect [ 3H]-GABA release. Nicotinic subunit-null mutant mouse experiments revealed that ACh-stimulated SuSC [ 3H]-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 [ 3H]-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. Novel α3α4β2 nicotinic subtype modulates superior colliculus GABA release.This study examined nicotinic acetylcholine receptor (nAChR) subtypes modulating GABA release in the superior colliculus, a region highly enriched in α-conotoxin MII-sensitive nAChRs. A novel functional α3α4β2 nAChR subtype was found to mediate superficial superior colliculus GABA release. This study confirms the expression of functional, non-α6β2-subtype, α-conotoxin MII-sensitive nAChRs in mammalian brain, and uncovers a new level of modulation of superior colliculus GABA release. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Publication Date

7-1-2012

Publication Title

Journal of Neurochemistry

ISSN

00223042

Volume

122

Issue

1

First Page

48

Last Page

57

Digital Object Identifier (DOI)

10.1111/j.1471-4159.2012.07759.x

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