Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2^* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

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 ␣6␤2* 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 ␣-conotoxin MII (␣-CtxMII) analog E11A to further investigate ␣6␤2* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with 125 I-␣-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct ␣6␤2* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with ϳ40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in ␣4 nAChR-null mutant mice. Because 125 I-␣-CtxMII binds primarily to ␣6␣4␤2␤3 and ␣6␤2␤3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the ␣4 knockout mice was the ␣6␣4␤2␤3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal ␣6␤2* 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 ␣6␣4␤2␤3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with ␣-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.

Nicotinic receptors as CNS targets for Parkinson's disease

“…The major nAChR subtypes appear similar to those in the rodent and include α6α4β2β3, α6β2β3 and α4β2 (Fig. 1), with only very low α7 nAChR expression [87,88]. There are some variations in the minor subtypes, with expression of α4α2β2 and α3β2* nAChRs in nonhuman primates, but not rodent striatum [87].…”

“…Subsequent receptor studies showed that only the very high affinity site was lost in striatum of α4 null mutant mice (Fig. 2) [88]. Altogether, these data suggest that the very high affinity site is the α6α4β2β3 receptor and the high affinity site the α6β2β3 subtype.…”

“…2). There was a preferential loss of the very high affinity E11A binding site (α6α4β2β3) in striatum of MPTP-treated mice, MPTP-treated monkeys and Parkinson's disease cases [88]. This selective loss of the α6α4β2β3 binding site correlated well with reductions in striatal dopamine transporter [88].…”

“…One such analog α-conotoxinMII E11A, in which the glutamic acid at position 11 is replaced with alanine [113], inhibited 125 I-α-conotoxinMII binding to striatum from mice, monkeys and humans in a biphasic manner (Fig. 2) [88]. These data indicate that α-conotoxinMII E11A distinguishes between a very high (fM) and high affinity (pM) α6β2* subtype.…”

“…2 and 3), while the α6β2β3 and α4β2 nAChR populations were reduced primarily with severe lesions (≥ 90%) ( Fig. 3; Table 2) [88]. The α6α4β2β3 subtype may thus provide a unique marker for dopamine nerve terminals that are particularly sensitive to nigrostriatal degeneration.…”