Nicotinic alpha5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers.
Neuronal nicotinic acetylcholine receptor subunit alpha5 mRNA is widely expressed in the CNS. An alpha5 gene polymorphism has been implicated in behavioral differences between mouse strains, and alpha5-null mutation induces profound changes in mouse acute responses to nicotine. In this study, we have examined the distribution and prevalence of alpha5* nicotinic acetylcholine receptor in mouse brain, and quantified the effects of alpha5-null mutation on pre-synaptic nicotinic acetylcholine receptor function (measured using synaptosomal (86)Rb(+) efflux) and overall [(125)I]epibatidine binding site expression. alpha5* nicotinic acetylcholine receptor expression was found in nine of fifteen regions examined, although < 20% of the total nicotinic acetylcholine receptor population in any region contained alpha5. Deletion of the alpha5 subunit gene resulted in localized loss of function (thalamus, striatum), which was itself confined to the DHbetaE-sensitive receptor population. No changes in receptor expression were seen. Consequently, functional changes must occur as a result of altered function per unit of receptor. The selective depletion of high agonist activation affinity sites results in overall nicotinic function being reduced, and increases the overall agonist activation affinity. Together, these results describe the receptor-level changes underlying altered behavioral responses to nicotine in nicotinic acetylcholine receptor alpha5 subunit-null mutants.
Brown
Robert W B
RW
Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
Collins
Allan C
AC
Lindstrom
Jon M
JM
Whiteaker
Paul
P
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000494:pharmacology; D009928:Organ Specificity; D011725:Pyridines / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; C523972:CHRNA5 protein, mouse; C082748:epibatidine