Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease

Gaby Ferrari-DiLeo, Deborah C. Mash, Donna D. Flynn

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Cortical M1 muscarinic receptor-G-protein coupling, high-affinity, guanine nucleotide-sensitive agonist binding (Flynn et al., 1991; Warpman et al., 1993) and muscarinic receptor-stimulated [3H]PIP2 hydrolysis (Ferrari-DiLeo and Flynn, 1993) are known to be defective in Alzheimer disease. Whether this defect reflects an alteration in the M1 muscarinic receptor, its respective guanine nucleotide binding (G) protein or both is not known. This study compares the number and both basal and muscarinic receptor-mediated function of G-proteins in synaptosomal membranes from cerebral cortical samples of age-matched control subjects and Alzheimer disease patients. Immuno-blotting with anti-Gαq/11 and anti-Gβ antibodies demonstrated no alteration in the number of these G-protein subunits in Alzheimer disease. Basal [35S]GTPγS binding and hydrolysis of [γ-32P]GTP by high-affinity GTPase also were not significantly altered in Alzheimer disease compared to control membrane samples. However, muscarinic agonist-stimulated GTPγS binding and GTP hydrolysis were significantly reduced (80-100%) in Alzheimer disease cortical samples. Diminished agonist-stimulated GTPγS binding and GTP hydrolysis corre-related with the loss of guanine nucleotide-sensitive, high-affinity agonist binding (KL/KH) ratio) to the M1 receptor subtype. These data provide further evidence for the loss of muscarinic receptor-G protein coupling in Alzheimer disease and support the hypothesis that muscarinic receptor-mediated cortical activation may be compromised in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)69-91
Number of pages23
JournalMolecular and Chemical Neuropathology
Volume24
Issue number1
DOIs
StatePublished - Jan 1 1995

Keywords

  • Alzheimer disease
  • G-proteins
  • GTP hydrolysis
  • GTPS binding
  • human brain
  • M1 muscarinic receptors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Molecular Biology

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