QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.025338v1 70/3/947    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marks, M. J. Articles by Collins, A. C. Search for Related Content PubMed PubMed Citation Articles by Marks, M. J. Articles by Collins, A. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CYTISINE

Deletion of the 7, 2, or 4 Nicotinic Receptor Subunit Genes Identifies Highly Expressed Subtypes with Relatively Low Affinity for [³H]Epibatidine

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado

Diversity of neuronal nicotinic acetylcholine receptor binding was measured using [³H]epibatidine after deletion of 7, 2, or 4 subunits. [³H]Epibatidine binding is distinctly biphasic. Densities of higher (K_d 0.02 nM) and lower (K_d 5 nM) affinity sites in whole brains of wild-type mice are very similar. Relative sensitivity to inhibition by cytisine or -bungarotoxin was used to evaluate pharmacological subsets of the higher- and loweraffinity sites, respectively. Deletion of each subunit had distinct effects on the binding sites. Deletion of 7 did not affect higher-affinity sites but reduced the numbers of lower-affinity sites. This reduction was confined to the [³H]epibatidine binding sites sensitive to inhibition by -bungarotoxin. Deletion of the 2 subunit had the largest effect. Higher-affinity sites sensitive to inhibition by cytisine were eliminated, and cytisine-resistant sites were reduced. Deletion of the 2 subunit also significantly reduced the number of lower-affinity sites insensitive to -bungarotoxin. 4 Gene deletion partially reduced cytisine-resistant and -bungarotoxin-resistant sites with lower and higher affinity for [³H]epibatidine, respectively. Gene deletion in four brain regions (thalamus, hippocampus, superior colliculus, and inferior colliculus) elicited changes generally similar to whole brain. However, relative expression of the binding sites differed among the regions. [³H]Cytisine and ¹²⁵I--bungarotoxin binding sites were eliminated by 2 and 7 gene deletion, respectively. These studies establish that the lower-affinity sites represent a structurally diverse set of sites that require expression of either 7, 2, or 4 subunits and extend and confirm previous classifications of the higher-affinity [³H]epibatidine binding sites.

Received for publication April 6, 2006.

Accepted for publication May 23, 2006.

Address correspondence to: Dr. Michael J. Marks, Institute for Behavioral Genetics, 447 UCB, University of Colorado, Boulder, CO 80309. E-mail: marksm{at}colorado.edu

This article has been cited by other articles:

				N. Innocent, P. D. Livingstone, A. Hone, A. Kimura, T. Young, P. Whiteaker, J. M. McIntosh, and S. Wonnacott {alpha}Conotoxin Arenatus IB[V11L,V16D] Is a Potent and Selective Antagonist at Rat and Human Native {alpha}7 Nicotinic Acetylcholine Receptors J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 529 - 537. [Abstract] [Full Text] [PDF]

				C. Gotti, M. Moretti, N. M. Meinerz, F. Clementi, A. Gaimarri, A. C. Collins, and M. J. Marks Partial Deletion of the Nicotinic Cholinergic Receptor {alpha}4 or {beta}2 Subunit Genes Changes the Acetylcholine Sensitivity of Receptor-Mediated 86Rb+ Efflux in Cortex and Thalamus and Alters Relative Expression of {alpha}4 and {beta}2 Subunits Mol. Pharmacol., June 1, 2008; 73(6): 1796 - 1807. [Abstract] [Full Text] [PDF]

				R. C. Drisdel, D. Sharp, T. Henderson, T. G. Hales, and W. N. Green High Affinity Binding of Epibatidine to Serotonin Type 3 Receptors J. Biol. Chem., April 11, 2008; 283(15): 9659 - 9665. [Abstract] [Full Text] [PDF]

				Y. Teper, D. Whyte, E. Cahir, H. A. Lester, S. R. Grady, M. J. Marks, B. N. Cohen, C. Fonck, T. McClure-Begley, J. M. McIntosh, et al. Nicotine-Induced Dystonic Arousal Complex in a Mouse Line Harboring a Human Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Mutation J. Neurosci., September 19, 2007; 27(38): 10128 - 10142. [Abstract] [Full Text] [PDF]

				M. I. Damaj, C. Fonck, M. J. Marks, P. Deshpande, C. Labarca, H. A. Lester, A. C. Collins, and B. R. Martin Genetic Approaches Identify Differential Roles for {alpha}4beta2* Nicotinic Receptors in Acute Models of Antinociception in Mice J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1161 - 1169. [Abstract] [Full Text] [PDF]