Coupling of ml Muscarinic Receptors to G Protein in... : Alzheimer Disease & Associated Disorders (original) (raw)
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Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida, U.S.A.
Abstract
Summary:
The potential usefulness of cholinergic replacement therapy for Alzheimer disease (AD) is dependent upon retention of postsynaptic muscarinic receptors and their transduction mechanisms long after the degeneration of cholinergic nerves. The receptors most clearly associated with cholinergic cerebral excitation are ml muscarinic receptors, which work via a G protein to activate phospholipase C. The ability of these receptors to couple to their associated G protein was assessed in the middle temporal gyrus of postmortem brains from persons with and without AD. A low concentration of [3H]- pirenzepine (1 nM) was used to label ml receptors preferentially. The affinity of the agonist, oxotremorine-M, for labeled receptors and the ability of these receptors to couple with G protein were assessed by competition between the agonist and 1 nM [3H]-pirenzepine in the presence and absence of guanine nucleotide. Brain tissue from 7 patients with AD and five age-matched controls showed very similar levels of labeled receptors, agonist affinities for the highand low-affinity states of ml receptors, and guanine nucleotide-sensitive high-affinity binding. It is concluded that the coupling of ml receptors to G protein is adequate to permit responses to exogenous muscarinic drugs in AD.
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