Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinson's disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine-M, and for nicotinic receptors with (-)-[3H]nicotine. In comparison with control tissues, choline acetyl-transferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinson's disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine-M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (-)-[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor II

Glimepiride is a novel sulfonylurea for the treatment of type II-diabetic patients exhibiting different receptor binding kinetics to β-cell membranes with 8–9-fold higher koff rate and 2.5–3-fold higher kon rate compared to glibenclamide (see accompanying paper (Müller, G. et al. (1994) Biochim. Biophys. Acta 1191, 267–277)). To elucidate the molecular basis for this differential behaviour of glimepiride and glibenclamide, direct photoaffinity labeling studies using β-cell tumor membranes were performed. [3H]Glimepiride was specifically incorporated into a membrane polypeptide of Mr = 65000 under conditions, which led to predominant labeling of a 140 kDa protein by [3H]glibenclamide (Kramer, W. et al. (1988) FEBS Lett. 229, 355–359). Labeling of the 140 kDa protein by [3H]glibenclamide was inhibited by unlabeled glimepiride and, vice versa, glibenclamide inhibited labeling of the 65 kDa protein by [3H]glimepiride. The 65 kDa protein was also specifically photolabeled by the sulfonylurea [125I]35623, whereas an 4-azidobenzoyl derivative of glibenclamide, N3-[3H]33055, exclusively labeled a 33 kDa protein. Competitive Scatchard analysis of [3H]glimepiride-binding and [3H]glibenclamide-binding to RINm5F cell membranes using glibenclamide and glimepiride, respectively, as heterologous displacing compounds yielded non-linear plots. These findings may be explained by cooperative interactions between the 140 and 65 kDa sulfonylurea-binding proteins. The possibility that sulfonylureas of different structure have different access to the 140 and 65 kDa receptor proteins due to the β-cell membrane barrier was investigated by photoaffinity labeling of solubilized β-cell membrane proteins. Interestingly, solubilization of β-cell tumor membranes led to a shift of specific [3H]glibenclamide binding from the 140 kDa to the 65 kDa binding protein, exclusively, and to an increased labeling of the 65 kDa protein by [3H]glimepiride. The labeling of a unique protein is in agreement with similar Kd values measured for both sulfonylurcas upon solubilization of β-cell tumor and RINm5F cell membranes (see accompanying paper). Furthermore, competitive Scatchard plots of [3H]glimepiride binding to solubilized RINm5F cell membrane proteins in the presence of glibenclamide and vice versa approximate linearity suggesting loss of cooperativity between the 140 kDa glibenclamide-binding and 65 kDa glimepiride-binding proteins upon solubilization. The physiological significance of the differential interaction of glimepiride and glibenclamide with different binding proteins was also substantiated by photoaffinity labeling of RINm5F cells leading to labeling of a 140 kDa protein by [3H]glibenclamide and of a 65 kDa protein by [3H]glimepiride. In conclusion, this report presents the first evidence that different sulfonylurea drugs bind to different components of the sulfonylurea receptor complex which are characterized by different accessibility for the drugs

Elastic Scattering of Pions From the Three-nucleon System

We examine the scattering of charged pions from the trinucleon system at a pion energy of 180 MeV. The motivation for this study is the structure seen in the experimental angular distribution of back-angle scattering for pi+ 3He and pi- 3H but for neither pi- 3He nor pi+ 3H. We consider the addition of a double spin flip term to an optical model treatment and find that, though the contribution of this term is non-negligible at large angles for pi+ 3He and pi- 3H, it does not reproduce the structure seen in the experiment.Comment: 15 pages + 5 figure

Ab-initio calculations of four-nucleon elastic scattering

We present microscopic calculations of low energy scattering observables in all possible four nucleon systems : n-3H, p-3He and p-3H. Results were obtained by solving Faddeev-Yakubovski equations in configuration space, appropriately modified to include Coulomb and three-nucleon forces

Universal Correlations in Pion-less EFT with the Resonating Group Model: Three and Four Nucleons

The Effective Field Theory "without pions" at next-to-leading order is used to analyze universal bound state and scattering properties of the 3- and 4-nucleon system. Results of a variety of phase shift equivalent nuclear potentials are presented for bound state properties of 3H and 4He, and for the singlet S-wave 3He-neutron scattering length a_0(3He-n). The calculations are performed with the Refined Resonating Group Method and include a full treatment of the Coulomb interaction and the leading-order 3-nucleon interaction. The results compare favorably with data and values from AV18(+UIX) model calculations. A new correlation between a_0(3He-n) and the 3H binding energy is found. Furthermore, we confirm at next-to-leading order the correlations, already found at leading-order, between the 3H binding energy and the 3H charge radius, and the Tjon line. With the 3H binding energy as input, we get predictions of the Effective Field Theory "without pions" at next-to-leading order for the root mean square charge radius of 3H of (1.6\pm 0.2) fm, for the 4He binding energy of (28\pm 2.5) MeV, and for Re(a_0(3He-n)) of (7.5\pm 0.6)fm. Including the Coulomb interaction, the splitting in binding energy between 3H and 3He is found to be (0.66\pm 0.03) MeV. The discrepancy to data of (0.10\mp 0.03) MeV is model independently attributed to higher order charge independence breaking interactions. We also demonstrate that different results for the same observable stem from higher order effects, and carefully assess that numerical uncertainties are negligible. Our results demonstrate the convergence and usefulness of the pion-less theory at next-to-leading order in the 4He channel. We conclude that no 4-nucleon interaction is needed to renormalize the theory at next-to-leading order in the 4-nucleon sector.Comment: 24 pages revtex4, including 8 figures as .eps files embedded with includegraphicx, leading-order results added, calculations include the LO three-nucleon interaction explicitly, comment on Wigner bound added, minor modification

Neutrino Breakup of A=3 Nuclei in Supernovae

We extend the virial equation of state to include 3H and 3He nuclei, and predict significant mass-three fractions near the neutrinosphere in supernovae. While alpha particles are often more abundant, we demonstrate that energy transfer cross-sections for muon and tau neutrinos at low densities are dominated by breakup of the loosely-bound 3H and 3He nuclei. The virial coefficients involving A=3 nuclei are calculated directly from the corresponding nucleon-3H and nucleon-3He scattering phase shifts. For the neutral-current inelastic cross-sections and the energy transfer cross sections, we perform ab-initio calculations based on microscopic two- and three-nucleon interactions and meson-exchange currents.Comment: 6 pages, 2 figures, minor additions, to appear in Phys. Rev.

A Precision Measurement of Nuclear Muon Capture on 3He

The muon capture rate in the reaction mu- 3He -> nu + 3H has been measured at PSI using a modular high pressure ionization chamber. The rate corresponding to statistical hyperfine population of the mu-3He atom is (1496.0 +- 4.0) s^-1. This result confirms the PCAC prediction for the pseudoscalar form factors of the 3He-3H system and the nucleon.Comment: 13 pages, 6 PostScript figure