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PMID: 17825262 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum.

Biochemical pharmacology ·Vol. 74 ·No. 8 ·2007-10-15 ·Pages 1235-46

Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC, Marks MJ

Abstract

This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [(125)I]-alpha-bungarotoxin and [(3)H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and alpha-conotoxin MII (alpha-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the alpha6 subunit (alpha4alpha6beta2beta3, alpha6beta2beta3, alpha6beta2) and bind alpha-CtxMII with high affinity. One of these three subtypes (alpha4alpha6beta2beta3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for alpha-CtxMII (alpha4beta2, alpha4alpha5beta2) are somewhat more numerous than the alpha6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions.

MeSH Terms
Animals Bridged Bicyclo Compounds, Heterocyclic/metabolism Bungarotoxins/metabolism Conotoxins/metabolism,pharmacology Corpus Striatum/chemistry Dopamine/metabolism Mice Pyridines/metabolism Receptors, Nicotinic/analysis,classification
Chemicals
Bridged Bicyclo Compounds, Heterocyclic Bungarotoxins Conotoxins Pyridines Receptors, Nicotinic alpha-conotoxin MII epibatidine Dopamine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Grady Sharon R
Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA. sharon.grady@colorado.edu
Salminen Outi
Laverty Duncan C
Whiteaker Paul
McIntosh J Michael
Collins Allan C
Marks Michael J
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Article Info
Journal
Biochemical pharmacology
Abbr.
Biochem Pharmacol
ISSN
0006-2952
DOI
10.1016/j.bcp.2007.07.032
Email
sharon.grady@colorado.edu
Published
2007-10-15
Epub
2007-00-27
Pages
1235-46
Language
English
Region
England
NLM ID
0101032
PMCID
PMC2735219
Subset
IM
Grants
NIDA NIH HHS · DA12242 · United States
NIDA NIH HHS · R01 DA012242-07 · United States
NIDA NIH HHS · R01 DA003194-25 · United States
NIDA NIH HHS · U19 DA019375-03 · United States
NIDA NIH HHS · R01 DA003194 · United States
NIDA NIH HHS · DA015663 · United States
NIDA NIH HHS · P30 DA015663-05 · United States
NIDA NIH HHS · P30 DA015663-02 · United States
NIDA NIH HHS · R01 DA012242 · United States
NIDA NIH HHS · P30 DA015663 · United States
NIDA NIH HHS · R01 DA003194-23 · United States
NIDA NIH HHS · R01 DA017279 · United States
NIDA NIH HHS · R01 DA003194-22 · United States
NIDA NIH HHS · P30 DA015663-01 · United States
NIDA NIH HHS · P30 DA015663-03 · United States
NIDA NIH HHS · U19 DA019375-02 · United States
NIDA NIH HHS · U19 DA019375-01A1 · United States
NIDA NIH HHS · R01 DA012242-08 · United States
NIDA NIH HHS · P30 DA015663-04 · United States
NIDA NIH HHS · U19 DA019375 · United States
NIDA NIH HHS · DA03194 · United States
NIDA NIH HHS · DA019375 · United States
NIDA NIH HHS · R01 DA003194-24 · United States
NIDA NIH HHS · R01 DA012242-06 · United States
External Links
PubMed source DOI: 10.1016/j.bcp.2007.07.032 PMC Full Text View journal details
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