Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus

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This chapter focuses on the muscarinic acetylcholine receptor (mAChR) family, whose five members participate in critical cholinergic functions including learning, memory, and attention, also presents their distribution. The five subtypes of mAChRs include M1, M2, M3, M4, and M5. Quantitative analysis of mAChR protein distribution performed in the rat brain using immunoprecipitations with subtype selective antibodies reveals that the M1, M2, and M4 mAChRs are the predominate mAChR subtypes expressed in the brain. M3 and M5 are also expressed throughout the brain, but in low abundance. In the human brain, M1 is the primary receptor in the frontal, temporal, parietal, and occipital cortical areas, representing 35–60% of total mAChRs. M2 is more abundant in the occipital cortex of human brain (36%) than in the frontal, temporal or parietal cortex (approximately 20%). M4 represents only approximately 20% of total the mAChRs in the human brain cortex. Electron microscopic studies in primate brain demonstrate that M1 localizes to postsynaptic dendrites and spines that associate with both asymmetric synapses and symmetric cholinergic synapses, indicating that M1 can modulate excitatory as well as cholinergic transmission. mAChRs expressed in the hippocampus, play a role in learning and memory, and degeneration of cholinergic projections to the hippocampus has been implicated in Alzheimer's disease.

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Muscarinic receptor expression in the brain

The diversity of mAChR subtypes and signaling pathways indicates that the localization of each receptor dictates the potential muscarinic responses to ACh in various cell types. Thus, considerable effort has been made to map the distribution of the mAChRs using a variety of approaches to detect each receptor. Many ligand autoradiographic binding studies have yielded insights into the relative abundance of the mAChR subtypes in brain (Cortes and Palacios, 1986, Mash and Potter, 1986, Spencer et

M1 is the major postsynaptic mAChR in the hippocampus

mAChRs expressed in the hippocampus, play a role in learning and memory (Jerusalinsky et al., 1997), and degeneration of cholinergic projections to the hippocampus has been implicated in Alzheimer's disease (Bartus et al., 1982, Gallagher and Colombo, 1995). Therefore, much research has focused on identifying the cellular mechanisms by which mAChR activation might contribute to learning and memory. One of the effects of mAChR activation in the hippocampus is potentiation of current through the

mAChR trafficking following acute stimulation

Following agonist stimulation, GPCRs undergo desensitization mediated by phosphorylation and binding of arrestin (Lefkowitz, 1998). In addition to preventing receptor interaction with the G protein, arrestin facilitates the binding of clathrin which induces receptor internalization via clathrin coated vesicles. The internalized receptors then traffic to early endosomes in which an acidic pH is thought to mediate a conformational change in the receptor, allowing interaction with phosphatases and

Summary

The M1, M2 and M4 subtypes of mAChRs are the predominant receptors in the CNS. These receptors activate a multitude of signaling pathways important for modulating neuronal excitability, synaptic plasticity and feedback regulation of ACh release. In addition, novel functions mediated by mAChRs are currently being discovered. These studies are greatly facilitated by the recent development of subtype selective toxins and mice lacking individual mAChR genes.

Studies in cell culture and the rodent

References (49)

  • S.T. Rouse et al.

    Muscarinic acetylcholine receptor subtype, m2: diverse functional implications of differential synaptic localization

    Life Sci.

    (1997)
  • S.T. Rouse et al.

    Localization of M(2) muscarinic acetylcholine receptor protein in cholinergic and non-cholinergic terminals in rat hippocampus

    Neurosci. Lett.

    (2000)
  • M.S. Shapiro et al.

    Identification of subtypes of muscarinic receptors that regulate Ca2+ and K+ channel activity in sympathetic neurons

    Life Sci.

    (2001)
  • D.G. Spencer et al.

    Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections

    Brain Res.

    (1986)
  • M.T. Vilaro et al.

    Muscarinic cholinergic receptors in the rat caudate-putamen and olfactory tubercle belong predominantly to the m4 class: in situ hybridization and receptor autoradiography evidence

    Neuroscience

    (1991)
  • L.A. Volpicelli et al.

    Rab5-dependent trafficking of the m4 muscarinic acetylcholine receptor to the plasma membrane, early endosomes, and multivesicular bodies

    J. Biol. Chem.

    (2001)
  • J.L. Whistler et al.

    Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction

    Neuron

    (1999)
  • A.A. Alcantara et al.

    Muscarinic m1 and m2 receptor proteins in local circuit and projection neurons of the primate striatum: anatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathways

    J. Comp. Neurol.

    (2001)
  • R.T. Bartus et al.

    The cholinergic hypothesis of geriatric memory dysfunction

    Science

    (1982)
  • J.L. Berkeley et al.

    Muscarinic activation of mitogen-activated protein kinase in PC12 cells

    J. Neurochem.

    (2000)
  • V. Bernard et al.

    Subcellular redistribution of m2 muscarinic acetylcholine receptors in striatal interneurons in vivo after acute cholinergic stimulation

    J. Neurosci.

    (1998)
  • V. Bernard et al.

    Regulation of the subcellular distribution of m4 muscarinic acetylcholine receptors in striatal neurons in vivo by the cholinergic environment: evidence for regulation of cell surface receptors by endogenous and exogenous stimulation

    J. Neurosci.

    (1999)
  • Bonner, T.I., Buckley, N.J., Young, A.C. and Brann, M.R. (1987) Identification of a family of muscarinic acetylcholine...
  • N.J. Buckley et al.

    Localization of a family of muscarinic receptor mRNAs in rat brain

    J. Neurosci.

    (1988)
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