Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease

Lebois, Evan P.; Thorn, Catherine A.; Edgerton, Jeremy R.; Popiolek, Michael; Xi, Shanshan

doi:10.1016/j.neuropharm.2017.11.018

Cited by 104 publications

(122 citation statements)

References 143 publications

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“…All five muscarinic receptors are expressed in the brain (Figure ) in both neurons and glial cells, but receptor abundance varies between regions. In most brain regions, the M1, M2 and M4 receptors are highly expressed, whereas M3 and M5 are typically expressed at much lower levels . This is in contrast to the expression profile in the periphery, where M2 and M3 are highly expressed .…”

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 88%

“…Cholinergic receptors are widely expressed throughout the body and are involved in a number of fundamental, central and peripheral processes . Although acetylcholine is arguably best known for its role in neuromuscular control, it also has pleiotropic effects as a neurotransmitter in the CNS.…”

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

“…In most brain regions, the M1, M2 and M4 receptors are highly expressed, whereas M3 and M5 are typically expressed at much lower levels . This is in contrast to the expression profile in the periphery, where M2 and M3 are highly expressed . The CNS expression pattern of mAChRs was first investigated in binding studies, utilizing radiolabelled ligands to distinguish between receptor subtypes in rat brains .…”

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

“…However, sensitivity issues prompted further studies, and in situ hybridization and immunohistochemical approaches have been used since to delineate the cellular distribution of the subtype mRNA and proteins, respectively. In the hippocampus, M1 and M4 are the most abundant receptor subtypes while M2 and M3 have a much lower expression (for anatomical differences within the hippocampus and a more detailed description of expression throughout the brain, please refer to Lebois et al 2018). In the neocortex, M1, M2 and M4 are the most abundant receptor subtypes.…”

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

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Muscarinic receptors in energy homeostasis: Physiology and pharmacology

Falk

Lund

Clemmensen

2019

Basic Clin Pharma Tox

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Despite increased awareness and intensified biomedical research efforts, the prevalence of obesity continues to rise worldwide. This is alarming, because obesity accelerates the progression of several chronic disorders, including type 2 diabetes, cancer and cardiovascular disease. Individuals who experience significant weight loss must combat powerful counter-regulatory energy homeostatic processes, and, typically, most individuals regain the lost weight. Therefore, decoding the neural mechanisms underlying the regulation of energy homeostasis is necessary for developing breakthroughs in obesity management. It has been known for decades that cholinergic neurotransmission both directly and indirectly modulates energy homeostasis and metabolic health. Despite this insight, the molecular details underlying the modulation remain ill-defined, and the potential for targeting cholinergic muscarinic receptors for treating metabolic disease is largely uncharted. In this MiniReview, we scrutinize the literature that has formed our knowledge of muscarinic acetylcholine receptors (mAChRs) in energy homeostasis. The role of mAChRs in canonical appetite-regulating circuits will be discussed as will the more indirect regulation of energy homoeostasis via neurocircuits linked to motivated behaviours and emotional states. Finally, we discuss the therapeutic prospects of targeting mAChRs for the treatment of obesity and type 2 diabetes. K E Y W O R D Sacetylcholine, energy metabolism, GPCR, muscarinic, obesity, pharmacology, type 2 diabetes | 67 FALK et AL.

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Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 88%

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

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Muscarinic receptors in energy homeostasis: Physiology and pharmacology

Falk

Lund

Clemmensen

2019

Basic Clin Pharma Tox

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“…To investigate whether the cGMP-PKG signaling pathway participated in the interplay of M1 receptor and AMPA receptor, soluble guanylate cyclase inhibitor 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) (10 mM) and PKG inhibitor KT5823 (10 mM) were used to pretreat neurons before CCh application. Phosphorylation of GluA1 at Ser845 was significantly increased in neurons pretreated with ODQ ( Fig.…”

Section: Adenylyl Cyclase and Pka Inhibitors Block Ser845 Phosphorylamentioning

confidence: 99%

M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP‐PKA and PI3K‐Akt

Zhao

et al. 2019

The FASEB Journal

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Ml muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2′,5′‐dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K‐Akt signaling induced by M1 receptor activation could be abolished by cAMP‐PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K‐Akt, by short‐term application of rapamycin attenuated the effects of Ml receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP‐PKA and PI3K‐Akt‐mTOR pathways but is irrelevant to protein synthesis.—Zhao, L.‐X., Ge, Y.‐H., Li, J.‐B., Xiong, C.‐H., Law, P.‐Y., Xu, J.‐R., Qiu, Y., Chen, H.‐Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP‐PKA and PI3K‐Akt. FASEB J. 33, 6622–6631 (2019). http://www.fasebj.org

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Cholinergics/Anticholinergics

Griffith¹,

Dukat²

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article covers classes of drugs and chemicals that act directly on muscarinic and nicotinic cholinergic receptors as agonists, antagonist, or allosteric modulators, together with an overview of the structures of muscarinic and nicotinic receptors. A brief history of the use of the small molecules muscarine, nicotine, and atropine to differentiate nicotinic and muscarinic receptors both of which respond to the neurotransmitter acetylcholine. This followed by discussion of the physical nature of the muscarinic G‐protein‐coupled‐receptor and the ligand‐gated‐ion‐channel nicotinic receptor. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors. Muscarinic antagonists are employed to treat disease states such as asthma, COPD, and overactive bladder. Muscarinic agonists have potential in the treatment of Alzheimer's disease. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented. Nicotinic agonists have been employed to assist in smoking cessation and have potential in treating Alzheimer's disease. Nicotinic antagonists have primarily been employed as neuromuscular blockers in surgery. The use of both positive and negative allosteric modulators of both muscarinic and nicotinic are discussed.

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Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease

Cited by 104 publications

References 143 publications

Muscarinic receptors in energy homeostasis: Physiology and pharmacology

Muscarinic receptors in energy homeostasis: Physiology and pharmacology

M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP‐PKA and PI3K‐Akt

Cholinergics/Anticholinergics

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