Current Advances in Allosteric Modulation of Muscarinic Receptors

Jakubík, Ján; El‐Fakahany, Esam E.

doi:10.3390/biom10020325

Cited by 38 publications

(17 citation statements)

References 89 publications

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“…In the established animal models, drugs have been used that block all five muscarinic receptor subtypes, hence, their systemic administration may induce side-effects in various organs [ 19 ]. The use of recently developed selective ligands for individual muscarinic receptors may reduce the systemic side effects [ 14 , 20 ], but is not likely to reduce the invasiveness and challenges of repeated drug administration. The use of genetically modified mice lacking individual muscarinic receptor subtypes may circumvent these problems.…”

Section: Discussionmentioning

confidence: 99%

Aged Mice Devoid of the M3 Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease

Musayeva

Jiang

Ruan

et al. 2021

IJMS

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The parasympathetic nervous system is critically involved in the regulation of tear secretion by activating muscarinic acetylcholine receptors. Hence, various animal models targeting parasympathetic signaling have been developed to induce dry eye disease (DED). However, the muscarinic receptor subtype (M1–M5) mediating tear secretion remains to be determined. This study was conducted to test the hypothesis that the M3 receptor subtype regulates tear secretion and to evaluate the ocular surface phenotype of mice with targeted disruption of the M3 receptor (M3R−/−). The experimental techniques included quantification of tear production, fluorescein staining of the ocular surface, environmental scanning electron microscopy, assessment of proliferating cells in the corneal epithelium and of goblet cells in the conjunctiva, quantification of mRNA for inflammatory cytokines and prooxidant redox enzymes and quantification of reactive oxygen species. Tear volume was reduced in M3R−/− mice compared to age-matched controls at the age of 3 months and 15 months, respectively. This was associated with mild corneal epitheliopathy in the 15-month-old but not in the 3-month-old M3R−/− mice. M3R−/− mice at the age of 15 months also displayed changes in corneal epithelial cell texture, reduced conjunctival goblet cell density, oxidative stress and elevated mRNA expression levels for inflammatory cytokines and prooxidant redox enzymes. The findings suggest that the M3 receptor plays a pivotal role in tear production and its absence leads to ocular surface changes typical for DED at advanced age.

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Section: Discussionmentioning

confidence: 99%

Aged Mice Devoid of the M3 Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease

Musayeva

Jiang

Ruan

et al. 2021

IJMS

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“…The cholesterol-binding site(s), on the other hand, is oriented towards membrane and may bind membrane soluble compounds that share structural similarity with cholesterol, like steroid hormones or neurosteroids (NS). This site may represent a novel target for allosteric modulation of muscarinic receptors 11 .…”

Section: Discussionmentioning

confidence: 99%

“…The common allosteric binding site of muscarinic receptors has been located between the second and third extracellular loop 10 . In contrast, the cholesterol-binding site is oriented towards membrane and may represent a novel target for allosteric modulation of muscarinic receptors with therapeutic potential 11 .…”

Section: Introductionmentioning

confidence: 99%

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

Dolejší

Szánti-Pintér

Chetverikov

et al. 2021

Preprint

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The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

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“…Muscarinic receptors (M 3 ) associated with the pancreatic β-cell membrane help for the liberation of glucosedependent insulin, which is triggered by acetylcholine (Jakubik and El-Fakahany, 2020). The report found that intraperitoneal administration of OA in Wistar rats results in decreases in fasting glycemia with subsequent action of enhancing the plasma insulin level in a parallel manner which suggests OA has acetylcholine enhancing effect at nerve endings.…”

Section: Role Of Oa In M3 Receptormentioning

confidence: 99%

The promising role of oleanolic acid in the management of diabetes mellitus: A review

Dash¹,

Pattnaik²,

Nityananda³

et al. 2021

J Appl Pharm Sci

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Oleanolic acid (OA) is a bioactive constituent and natural triterpenoid with a pentacyclic structure. OA possesses beneficial effects against diabetes and other metabolic disorder by undergoing a more complex and multifactorial pathway. It activates the insulin response, protects the capability and existence of pancreatic β-cells and also gives protection against diabetic difficulties. The molecular mechanism of antidiabetic activities of OA involve modulation of transduction mechanisms includes oxidative stress-induced hepatic insulin resistance, phosphorylation of extracellular signal-related kinase, protective effect on mitochondrial function, regulates NF-kappa B, suppresses polyol mechanism, formation of advanced glycation end products, activation of M3 muscarinic receptors, and activation of G proteincoupled bile acid receptor.. Thus, the utilization of effective drug or food material carrying OA might be an effective way to control diabetes. Till now, limited clinical studies have been performed to explore the use of OA in the management of diabetes mellitus. However, due to their potential therapeutic activities, OA deserves special attention. In this present review article, we have summarized the antidiabetic potential of OA reported mainly from the period of 2015-2020 with a notable emphasis on the molecular mechanisms. We have searched Google Scholar, medical databases, and websites using related keywords like OA, insulin, diabetes mellitus, herbal medicine, or a combination of them. To qualify for inclusion, the herbal plants should have tremendous antidiabetic activities, established with biomarkers with limited adverse effects.

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Current Advances in Allosteric Modulation of Muscarinic Receptors

Cited by 38 publications

References 89 publications

Aged Mice Devoid of the M3 Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease

Aged Mice Devoid of the M3 Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

The promising role of oleanolic acid in the management of diabetes mellitus: A review

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