Localization of M2 muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus

doi:10.1016/S0304-3940(00)01011-9

Neuroscience Letters

Volume 284, Issue 3, 28 April 2000, Pages 182-186

https://doi.org/10.1016/S0304-3940(00)01011-9 Get rights and content

Abstract

The muscarinic receptor family (M₁–M₄) mediates cholinergic modulation of hippocampal transmission. Pharmacological and physiological studies have indicated that a presynaptic receptor on cholinergic terminals plays a key role in regulating ACh release, although the molecular identity of this subtype is uncertain. In this study, the localization of the M₂ receptor is described in detail for the pyramidal cell layer in the CAl region of the hippocampus. Electron microscopic analysis of M₂ immunoreactivity in this area revealed mainly presynaptic expression of this subtype. Double-labeling experiments using antibodies to M₂ and to the vesicular acetylcholine transporter, a novel, specific marker of cholinergic terminals, were used to investigate the nature of these presynaptic receptors. These studies have revealed that M₂ is located in cholinergic and non-cholinergic terminals. This is the first direct anatomical evidence that suggests that M₂ may indeed function as a cholinergic autoreceptor in the hippocampus. The distribution of the M₂ receptor in non-cholinergic terminals also suggests functional roles for M₂ as a presynaptic heteroreceptor.

Section snippets

Acknowledgements

This study was supported by RO1 N530454 (A.I.L.). S.T.R. and M.L.G. were recipients of pre-doctoral National Research Service Awards from the NIMH (F31 MH11186-02, S.T.R.; F31 MH11474-01, M.L.G.). We would like to acknowledge Dr Howard Rees for expert technical assistance.

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Citation Excerpt :
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Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M₁ - M₅, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype-selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification.
This article is part of the Special Issue entitled ‘Neuropharmacology on Muscarinic Receptors’.
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Localization of M2 muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus

Abstract

Section snippets

Acknowledgements

Cell Biol. Int. Rep.

M2: diverse functional implications of differential synaptic localization, Life Sci.

Brain Res. Bull.

Neuroscience

Cholinergic modulation of synaptic inhibition in the guinea pig hippocampus in vitro: excitation of GABAergic interneurons and inhibition of GABA-release

J. Neurophysiol.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease

Arch. Neurol.

Regional selectivity of a gamma-aminobutyric acid-induced acetylcholine release sensitive to inhibitors of gamma-aminobutyric acid uptake

J. Neurochem.

Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells

Mol. Pharmacol.

Alzheimer's disease: a disorder of cortical cholinergic innervation

Science

Antagonist binding profiles of five cloned human muscarinic receptor subtypes

J. Pharmacol. Exp. Ther.

Localization of M₂ muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus

M₂: diverse functional implications of differential synaptic localization, Life Sci.