M3 muscarinic acetylcholine receptor in cardiology and oncology

Patanè, Salvatore

doi:10.1016/j.ijcard.2014.09.178

Cited by 38 publications

(22 citation statements)

References 91 publications

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“…We focused on the muscarinic acetylcholine receptor M3R—the only member of the acetylcholine (Ach) GPCR group expressed in HEK293 cells 16 . In vivo, M3R is expressed in a number of tissues 17 and regulates many important physiological and pathological conditions, including smooth muscle contraction and dilation of peripheral blood vessels 18 , cardiac function and heart disease 19 , whole-body metabolic activities 20 , insulin secretion 21 , bone formation 22 , tumor formation in the gastrointestinal tract 23 , T-cell dysfunctioning in Sjögren’s syndrome 24 , and others 25 . The crystal structure of M3R bound in a complex with its antagonist tiotropium (clinically used for bronchodilation and against chronic obstructive pulmonary disease 26 ) paves the way for rational design of drugs targeting this GPCR 27 .…”

Section: Resultsmentioning

confidence: 99%

High capacity in G protein-coupled receptor signaling

et al. 2018

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G protein-coupled receptors (GPCRs) constitute a large family of receptors that activate intracellular signaling pathways upon detecting specific extracellular ligands. While many aspects of GPCR signaling have been uncovered through decades of studies, some fundamental properties, like its channel capacity—a measure of how much information a given transmission system can reliably transduce—are still debated. Previous studies concluded that GPCRs in individual cells could transmit around one bit of information about the concentration of the ligands, allowing only for a reliable on or off response. Using muscarinic receptor-induced calcium response measured in individual cells upon repeated stimulation, we show that GPCR signaling systems possess a significantly higher capacity. We estimate the channel capacity of this system to be above two, implying that at least four concentration levels of the agonist can be distinguished reliably. These findings shed light on the basic principles of GPCR signaling.

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Section: Resultsmentioning

confidence: 99%

High capacity in G protein-coupled receptor signaling

et al. 2018

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“…Further study showed that M 3 R plays a critical role in glucose homoeostasis [68,70]. Some research reported that M 3 R activation by choline, an ACh precursor and metabolite, has a protective effect on both cardiac and vascular endothelial cells by enhanced phosphorylation of Connexin-43, Ca 2+ /calmodulin-dependent protein kinase II (CaMK II), and endogenous antioxidant capacity, and diminished Ca 2+ overload [33,34,[71][72][73]. Moreover, M 3 R activation decreased Bcl-2 expression and cytochrome C release and attenuated mitochondria-mediated apoptosis [22,72].…”

Section: Discussionmentioning

confidence: 99%

Vagal nerve stimulation improves mitochondrial dynamics via an M₃ receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia

Xue

Sun

et al. 2016

J Cellular Molecular Medi

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Mitochondrial dynamics—fission and fusion—are associated with ischaemic heart disease (IHD). This study explored the protective effect of vagal nerve stimulation (VNS) against isoproterenol (ISO)‐induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin‐related peptide1 (Drp1) and mitochondrial fission protein1 (Fis‐1)) and decreased the expression of fusion proteins (optic atrophy‐1 (OPA1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis‐1, OPA1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore (MPTP) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO. Moreover, VNS activated AMP‐activated protein kinase (AMPK), which was accompanied by phosphorylation of Ca2+/calmodulin‐dependent protein kinase kinase β (CaMKKβ) during myocardial ischaemia. Treatment with subtype‐3 of muscarinic acetylcholine receptor (M3R) antagonist 4‐diphenylacetoxy‐N‐methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M3R/CaMKKβ/AMPK signalling are involved in mediating beneficial effects of VNS. This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M3R/CaMKKβ/AMPK pathway, to attenuate ISO‐induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD.

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“… 7 , 8 , 9 Cardiac muscarinic stimulation causes slowing of heart rate through direct G protein-dependent regulation of ion channel activity and modulation of cyclic adenosine monophosphate (cAMP)-mediated responses. 8 Ach-induced stimulation of muscarinic receptors in arteries causes contraction and relaxation depending on the vascular bed and the integrity of the endothelium. 7 The primary muscarinic response in intact vessels is vasodilation caused by endothelial M3Rs (as well as M2Rs and M5Rs), which increase endothelial nitric oxide synthase (eNOS)-induced production of NO.…”

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confidence: 99%