Abstract
Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the α6β2* nicotinic acetylcholine receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum (*denotes the presence of possible additional subunits). In this study, we used a novel α-conotoxin MII (α-CtxMII) analog E11A to further investigate α6β2* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with 125I-α-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct α6β2* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with ∼40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in α4 nAChR-null mutant mice. Because 125I-α-CtxMII binds primarily to α6α4β2β3 and α6β2β3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the α4 knockout mice was the α6α4β2β3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal α6β2* populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the α6α4β2β3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with α-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.
Footnotes
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This work was supported by National Institutes of Health grants NS42091 and NS47162 (to M.Q.) and National Institutes of Health grant MH53631 (to J.M.M.).
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; α-CtxMII, α-conotoxin MII; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; RTI-121, 3β-(4-iodophenyl)tropane-2β-carboxylic acid; BSA, bovine serum albumin.
- Received March 9, 2007.
- Accepted April 4, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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