Overview of Muscarinic Receptor Subtypes

Eglen, Richard M.

doi:10.1007/978-3-642-23274-9_1

Cited by 91 publications

(88 citation statements)

References 154 publications

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“…1). The lack of frequency-driving ability of cholinergic neurons is not surprising in light of the slow, second messenger-mediated mechanism of muscarinic receptors (41). Increasing the frequency of optogenetic stimulation simply increased theta power; this effect can be explained by the higher discharge rates of the septal cholinergic cells.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

Vandecasteele

Varga

Berényi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

321

317

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Theta oscillations in the limbic system depend on the integrity of the medial septum. The different populations of medial septal neurons (cholinergic and GABAergic) are assumed to affect different aspects of theta oscillations. Using optogenetic stimulation of cholinergic neurons in ChAT-Cre mice, we investigated their effects on hippocampal local field potentials in both anesthetized and behaving mice. Cholinergic stimulation completely blocked sharp wave ripples and strongly suppressed the power of both slow oscillations (0.5-2 Hz in anesthetized, 0.5-4 Hz in behaving animals) and supratheta (6-10 Hz in anesthetized, 10-25 Hz in behaving animals) bands. The same stimulation robustly increased both the power and coherence of theta oscillations (2-6 Hz) in urethane-anesthetized mice. In behaving mice, cholinergic stimulation was less effective in the theta (4-10 Hz) band yet it also increased the ratio of theta/slow oscillation and theta coherence. The effects on gamma oscillations largely mirrored those of theta. These findings show that medial septal cholinergic activation can both enhance theta rhythm and suppress peri-theta frequency bands, allowing theta oscillations to dominate.S ubcortical neuromodulators play a critical role in shifting states of the brain (1, 2). State changes can occur both during sleep and in the waking animal and are instrumental in affecting local circuit computation that supports various functions, including attention, learning, memory, and action (3-5). The septo-hippocampal cholinergic system has been hypothesized to play a critical role in setting network states in the limbic system (4, 6). ACh can affect both short-and long-term plasticity of synaptic connections and provide favorable conditions for encoding information (7-9). These plastic states are associated with hippocampal theta oscillations (10). High theta states are characterized by increased release of ACh that varies in a task-dependent manner on the time scale of seconds (11-13). In contrast, reduced cholinergic activity allows effective spread of excitation in the recurrent CA3 network, giving rise to synchronous sharp wave ripples (SPW-R) (14-16).Inactivation of the medial septum (MS)/diagonal band of Broca abolishes theta oscillations in the hippocampus and entorhinal cortex (17) and results in severe learning deficit (18,19). Similarly, selective toxin lesion of septal cholinergic neurons produces a several-fold decrease of theta power but not its frequency (20). The phase of the local field potentials (LFP) theta oscillations shifts from the septal to the temporal pole and in the CA3-CA1 axis by ∼180° (21, 22). Thus, at each point in time neurons residing at different locations of the three-dimensional structure of the hippocampus spike at different theta phases yet are bound together by the global theta signal. These numerous sources of theta generators are believed to be coordinated by the reciprocal connections between the septum and hippocampus (23), but the nature of this spatial-temporal coordination is n...

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Section: Discussionmentioning

confidence: 99%

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

Vandecasteele

Varga

Berényi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

321

317

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“…[3][4][5][6][7][8] Direct and subtypeselective activation of ACh receptors are therefore considered to be better approaches to treat cognitive impairment and BPSD in AD. 9) Muscarinic ACh receptors (mAChRs) belong to the rhodopsin-like G-protein-coupled receptor (GPCR) family [10][11][12][13] and are classified into five subtypes (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…M 1 , M 4 , and M 5 mAChRs are predominantly expressed in the brain, while M 2 and M 3 mAChRs are highly distributed in peripheral tissues. 12,14) Among these subtypes, M 1 and M 4 mAChRs are thought to be promising targets for the treatment of AD and schizophrenia. These assumptions are supported by knockout mice studies, as well as by results from clinical trials of xanomeline, an M 1 /M 4 mAChRs-preferring agonist.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Development of Muscarinic Acetylcholine M<sub>4</sub> Activators as Promising Therapeutic Agents for CNS Diseases

Takai

Enomoto

2018

Chem. Pharm. Bull.

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Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M 4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M 4 -deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M 1 /M 4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M 4 mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M 4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M 4 mAChR structural information and structure-activity relationship studies. These findings indicate that selective M 4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.

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“…The five muscarinic cholinergic receptor subtypes (mAChRs; M1-M5) play prominent roles in the central and parasympathetic nervous systems, and are potential therapeutic targets (Eglen, 2012). Decades of research have enriched a wide collection of high-affinity and efficacious molecules competing with the neurotransmitter acetylcholine (ACh) for binding to muscarinic receptors.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands

et al. 2013

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Bitopic binding properties apply to a variety of muscarinic compounds that span and simultaneously bind to both the orthosteric and allosteric receptor sites. We provide evidence that fluorescent pirenzepine derivatives, with the M1 antagonist fused to the boron-dipyrromethene [Bodipy (558/568)] fluorophore via spacers of varying lengths, exhibit orthosteric/ allosteric binding properties at muscarinic M1 receptors. This behavior was inferred from a combination of functional, radioligand, and fluorescence resonance energy transfer binding experiments performed under equilibrium and kinetic conditions on enhanced green fluorescent protein-fused M1 receptors. Although displaying a common orthosteric component, the fluorescent compounds inherit bitopic properties from a linkerguided positioning of their Bodipy moiety within the M1 allosteric vestibule. Depending on linker length, the fluorophore is allowed to reach neighboring allosteric domains, overlapping or not with the classic gallamine site, but distinct from the allosteric indolocarbazole "WIN" site. Site-directed mutagenesis, as well as molecular modeling and ligand docking studies based on recently solved muscarinic receptor structures, further support the definition of two groups of Bodipypirenzepine derivatives exhibiting distinct allosteric binding poses. Thus, the linker may dictate pharmacological outcomes for bitopic molecules that are hardly predictable from the properties of individual orthosteric and allosteric building blocks. Our findings also demonstrate that the fusion of a fluorophore to an orthosteric ligand is not neutral, as it may confer, unless carefully controlled, unexpected properties to the resultant fluorescent tracer. Altogether, this study illustrates the importance of a "multifacet" experimental approach to unravel and validate bitopic ligand binding mechanisms.

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Overview of Muscarinic Receptor Subtypes

Cited by 91 publications

References 154 publications

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

Discovery and Development of Muscarinic Acetylcholine M<sub>4</sub> Activators as Promising Therapeutic Agents for CNS Diseases

Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands

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