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PubMed: 24590577

Title
M1 muscarinic acetylcholine receptor in Alzheimer's disease.
Journal
Neuroscience bulletin
Volume
30
Issue
None
Pages
295-307
Date
2014-04-01
Authors
Bu G | Jiang S | Li Y | Xu H | Zhang C | Zhang YW | Zhao Y

Evidence 0be6ea4fce
JSON

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle.

a(CHEBI:"amyloid-beta") decreases complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases act(p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) increases a(HBP:"sAPP-alpha") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) increases bp(GO:"signal transduction") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 9567ea270c
JSON

Nevertheless, a compound developed later, TBPB, selectively activates M1 mAChR in cell lines and shows no agonist activity in any other mAChR subtype. Interestingly, TBPB also potentiates the NMDA-evoked current in hippocampal pyramidal neurons, which is considered to be important for the effect of M1 mAChR on improving cognition. In addition, TBPB shifts the processing of APP in the non-amyloidogenic direction and thereafter decreases neurotoxic Abeta production vitro[120].

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Pyramidal Cells

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") increases act(p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") increases bp(GO:"NMDA selective glutamate receptor signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Pyramidal Cells

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Pyramidal Cells

act(p(HGNC:CHRM1)) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Pyramidal Cells

Evidence e270a34199
JSON

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels

a(CHEBI:acetylcholine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

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a(CHEBI:acetylcholine) increases act(p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) View Subject | View Object

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p(HGNC:CHAT) decreases a(CHEBI:acetylcholine) View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases p(HGNC:CHAT) View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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Evidence a16a3993e4
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M4 mAChR is also involved in the pathology of Parkinson’s disease, which is associated with the loss of dopaminergic neurons projecting to the striatum and an imbalance between cholinergic and dopaminergic systems. In the corpus striatum, M4 mAChR is closely co-localized with dopamine receptors on striatal-projecting neurons and the striatal M4 mAChR inhibits dopamine D1 receptor function. Mice lacking M4 mAChR show increased locomotor activity and enhanced dopamine D1 receptor-mediated effects[55]. Consequently, selective M4 mAChR antagonists, such as benzoxazines, have been developed for the treatment of Parkinson’s disease

a(CHEBI:benzoxazine) decreases path(MESH:"Parkinson Disease") View Subject | View Object

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p(HGNC:CHRM4) association path(MESH:"Parkinson Disease") View Subject | View Object

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p(HGNC:CHRM4) decreases act(p(HGNC:DRD1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Corpus Striatum

p(MGI:Chrm4) decreases bp(GO:"locomotor rhythm") View Subject | View Object

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p(MGI:Chrm4) decreases act(p(MGI:Drd1)) View Subject | View Object

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path(MESH:"Parkinson Disease") association p(HGNC:CHRM4) View Subject | View Object

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path(MESH:"Parkinson Disease") decreases act(a(MESH:"Dopaminergic Neurons")) View Subject | View Object

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Evidence db730835a2
JSON

Stimulation of M1 mAChR by two agonists, carbachol and AF102B, time- and dose-dependently decreases tau phosphorylation in PC12 cells[81]. Chronic treatment with AF267B also alleviates tau pathology in 3×Tg AD mice, possibly by activating PKC and inhibiting GSK-3beta

a(CHEBI:carbachol) increases act(p(HGNC:CHRM1)) View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
PC12

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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a(MESH:cevimeline) increases act(p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

act(p(HGNC:CHRM1)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

Evidence a7619bead5
JSON

Administration of AF267B and AF102B (Cevimeline, EVOXACTM), an M1 mAChRselective agonist once prescribed for the treatment of Sjogren’s syndrome, decreases Abeta42 levels in the cerebral spinal fluid (CSF) of rabbits without affecting APP

a(CHEBI:cevimeline) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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MeSH
Cerebrospinal Fluid

a(CHEBI:cevimeline) decreases path(MESH:"Sjogren's Syndrome") View Subject | View Object

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Annotations
MeSH
Cerebrospinal Fluid

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid

Evidence e63ecfd4a3
JSON

Moreover, AF102B administration decreased the total CSF Abeta levels by 22% in 14 of 19 AD patients without affecting sAPPalpha levels. However, AF102B has serious side effects including gastrointestinal symptoms, diaphoresis, confusion, diarrhea, and asthenia

a(CHEBI:cevimeline) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) causesNoChange a(HBP:"sAPP-alpha") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) increases path(MESH:Confusion) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) increases path(MESH:Diarrhea) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) increases path(MESH:Asthenia) View Subject | View Object

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Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) increases path(MESH:"Gastrointestinal Diseases") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

Evidence c44d54ecf2
JSON

M4 mAChR is mainly expressed in the corpus striatum in the CNS and on various prejunctional nerve terminals in the periphery. M4 mAChR has been suggested to play a role in psychosis and to be a promising target for the treatment of schizophrenia[52]. Indeed, the mixed M1/M4 mAChR agonist xanomeline has antipsychotic effects, and M4 mAChR-knockout mice display increased sensitivity to the disruptive effects of phencyclidine, a drug of abuse

a(CHEBI:xanomeline) decreases path(MESH:"Psychotic Disorders") View Subject | View Object

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a(MESH:"Corpus Striatum") association p(HGNC:CHRM4) View Subject | View Object

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p(HGNC:CHRM4) association a(MESH:"Corpus Striatum") View Subject | View Object

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p(HGNC:CHRM4) association path(MESH:"Psychotic Disorders") View Subject | View Object

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p(MGI:Chrm4) decreases act(a(CHEBI:phencyclidine)) View Subject | View Object

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path(MESH:"Psychotic Disorders") association p(HGNC:CHRM4) View Subject | View Object

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Evidence b617d2e8c1
JSON

One example is xanomeline, an mAChR agonist with selectivity for the M1 and M4 subtypes. Xanomeline improves working memory in rodents and improves cognition and reduces psychotic episodes in AD patients, but it failed during phase-II clinical trial because of serious side-effects, probably due to simultaneous activation of M1 and M4 mAChRs (M4 > M1)

a(CHEBI:xanomeline) increases bp(GO:memory) View Subject | View Object

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a(CHEBI:xanomeline) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:xanomeline) increases act(p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:xanomeline) increases act(p(HGNC:CHRM4)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence 7e03684e01
JSON

NFTs are formed by accumulation of hyperphosphorylated tau protein[7, 8]. Tau is a microtubule-binding protein whose function is to stabilize microtubules and facilitate fast axonal transport. Once highly phosphorylated, tau dissociates from microtubules and is prone to aggregate, forming paired helical fi laments that aggregate into NFTs

a(HBP:"Tau aggregates") increases path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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p(HGNC:MAPT) regulates bp(GO:"microtubule anchoring") View Subject | View Object

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p(HGNC:MAPT) regulates bp(GO:"axonal transport") View Subject | View Object

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Evidence d80df49944
JSON

Senile plaques consist of deposits of small peptides called beta-amyloid (Abeta). Multiple lines of evidence suggest that the overproduction/ aggregation of neurotoxic Abeta in vulnerable brain regions is the primary cause of AD

a(HBP:"amyloid-beta aggregates") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

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a(HBP:"amyloid-beta aggregates") increases path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence c14aad975b
JSON

Abeta, an important player in AD, is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases: APP is cleaved by beta-secretase (BACE1) to generate the large secreted derivative sAPPbeta and the membrane-bound APP C-terminal fragment-beta; the latter can be further cleaved by gamma-secretase to generate Abeta and APP intracellular domain. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain, which precludes Abeta production and instead generates secreted sAPPalpha that has been shown to be neuroprotective

a(HBP:"sAPP-alpha") increases bp(MESH:Neuroprotection) View Subject | View Object

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complex(FPLX:"Gamma_secretase") increases deg(a(HBP:C99)) View Subject | View Object

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complex(FPLX:"Gamma_secretase") increases a(CHEBI:"amyloid-beta") View Subject | View Object

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complex(FPLX:"Gamma_secretase") increases a(HBP:AICD) View Subject | View Object

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p(HGNC:BACE1) increases deg(p(HGNC:APP)) View Subject | View Object

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p(HGNC:BACE1) increases a(HBP:"sAPP-beta") View Subject | View Object

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p(HGNC:BACE1) increases a(HBP:C99) View Subject | View Object

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p(HGNC:ADAM10) increases deg(p(HGNC:APP)) View Subject | View Object

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p(HGNC:ADAM10) increases a(HBP:"sAPP-alpha") View Subject | View Object

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Evidence bb2601e7df
JSON

After brucine, several other M1-PAMs have been discovered, including VU0029767, VU0090157, and benzyl quinolone carboxylic acid (BQCA)[115-117]. These compounds do not activate M1 mAChR directly but greatly increase the affi nity of ACh for the M1 subtype. In addition, BQCA is effective in restoring discrimination reversal learning in a mouse model of AD and regulating nonamyloidogenic APP processing[117].

a(HBP:VU0029767) increases complex(a(CHEBI:acetylcholine), p(HGNC:CHRM1)) View Subject | View Object

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a(HBP:VU0090157) increases complex(a(CHEBI:acetylcholine), p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases complex(a(CHEBI:acetylcholine), p(HGNC:CHRM1)) View Subject | View Object

Appears in Networks:

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(MESH:"1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid") regulates bp(HBP:"APP processing") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence e8a879434c
JSON

During the past few years, the M1 mAChR allosteric agonists VU0184670 and VU0357017 have been screened out, and have more exciting properties. Both compounds have high solubility in aqueous solutions as well as good CNS penetration, without any agonist or antagonist activity for the M2 and M5 subtypes

a(HBP:VU0184670) increases act(p(HGNC:CHRM1)) View Subject | View Object

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a(MESH:VU0357017) increases act(p(HGNC:CHRM1)) View Subject | View Object

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Evidence 18b453b07a
JSON

Moreover, VU0184670 potentiates neuronal NMDAR-mediated currents in hippocampal brain slices and VU0357017 reverses the cognitive deficits induced by an mAChR antagonist in a contextual fear conditioning paradigm, exhibiting improvement of hippocampus-dependent learning[110, 123].

a(HBP:VU0184670) increases bp(GO:"NMDA selective glutamate receptor signaling pathway") View Subject | View Object

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Annotations
MeSH
Hippocampus

a(MESH:VU0357017) decreases path(MESH:"Cognitive Dysfunction") View Subject | View Object

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Annotations
MeSH
Hippocampus

a(MESH:VU0357017) increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 5bc99deeca
JSON

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner.

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(MGI:Bace1) View Subject | View Object

Appears in Networks:

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

bp(GO:"MAPK cascade") increases p(HGNC:BACE1) View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) increases act(p(FPLX:PKC)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) increases p(HGNC:BACE1) View Subject | View Object

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p(HGNC:CHRM1) regulates p(HGNC:BACE1) View Subject | View Object

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act(p(HGNC:CHRM1)) increases bp(GO:"MAPK cascade") View Subject | View Object

Appears in Networks:

complex(p(HGNC:BACE1), p(HGNC:CHRM1)) increases deg(p(HGNC:BACE1)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PKC)) increases p(HGNC:BACE1) View Subject | View Object

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Evidence 76a7dc80f1
JSON

Chronic treatment with AF267B reduces Abeta plaques and tau hyperphosphorylation and rescues learning and memory impairments in 3×Tg AD mice

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence c28fbc2135
JSON

In mice with scopolamine-induced deficits, PQCA, a selective M1 mAChR positive allosteric modulator[87], improves not only recognition memory, spatial working memory, and executive function, but also blood-flow in the frontal cortex, though the mechanism is not yet clear.

a(MESH:"1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid") increases act(p(MGI:Chrm1)) View Subject | View Object

Appears in Networks:

a(MESH:"1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid") increases bp(GO:memory) View Subject | View Object

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a(MESH:"1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid") increases path(MESH:"Executive Function") View Subject | View Object

Appears in Networks:

Evidence c2daf696c9
JSON

Compound 77-LH-28-1 shows relatively higher selectivity for the M1 than for the M2, M4, and M5 subtypes, but retains weak agonist activity for M3 mAChR at high doses. Electrophysiological studies indicate that 77-LH-28-1 increases the activity of hippocampal CA1 pyramidal cells both in vitro and in vivo. Interestingly, unlike other normal orthosteric agonists, 77-LH-28-1 appears to selectively activate M1 mAChR in a distinct signaling pathway

a(MESH:"1-(3-(4-butyl-1-piperidinyl)propyl)-3,4-dihydro-2(1H)-quinolinone") increases act(p(HGNC:CHRM1)) View Subject | View Object

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a(MESH:"1-(3-(4-butyl-1-piperidinyl)propyl)-3,4-dihydro-2(1H)-quinolinone") increases act(a(MESH:"Pyramidal Cells")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

Evidence e07cd847c4
JSON

The M1 mAChR agonist AC-260584 was recently reported to be orally bioavailable with favorable antipsychotic and cognition-enhancing effects[118, 122].

a(MESH:"4-(3-(4-butylpiperidin-1-yl)propyl)-7-fluoro-4H-benzo(1,4)oxazin-3-one") increases bp(GO:cognition) View Subject | View Object

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a(MESH:"4-(3-(4-butylpiperidin-1-yl)propyl)-7-fluoro-4H-benzo(1,4)oxazin-3-one") association a(MESH:"Antipsychotic Agents") View Subject | View Object

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a(MESH:"Antipsychotic Agents") association a(MESH:"4-(3-(4-butylpiperidin-1-yl)propyl)-7-fluoro-4H-benzo(1,4)oxazin-3-one") View Subject | View Object

Appears in Networks:

Evidence 5816bd203e
JSON

Members of the mAChR family are widely expressed in various regions in the central nervous system (CNS) and in the peripheral system. They play crucial roles in diverse physiological processes such as memory, attention, nociception, motor control, sleep-wake cycles, and cardiovascular, renal, and gastrointestinal functions

a(MESH:"Cardiovascular System") association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

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a(MESH:"Gastrointestinal Tract") association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

a(MESH:Kidney) association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

bp(GO:"circadian sleep/wake cycle") association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

bp(GO:memory) association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association bp(GO:memory) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association path(MESH:Attention) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association path(MESH:Nociception) View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association bp(GO:"circadian sleep/wake cycle") View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association a(MESH:"Cardiovascular System") View Subject | View Object

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association a(MESH:Kidney) View Subject | View Object

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p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association a(MESH:"Gastrointestinal Tract") View Subject | View Object

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path(MESH:Attention) association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

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path(MESH:Nociception) association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

Evidence 835d41d6c2
JSON

Among the mAChR family members, the M1 subtype makes up 50–60% of the total and is predominantly expressed in all major areas of the forebrain, including the hippocampus, cerebral cortex, corpus striatum, and thalamus[36-38]. M1 mAChR-knockout mice show a series of cognitive defi cits and impairments in long-term potentiation, indicating that the M1 subtype is physiologically linked to multiple functions such as synaptic plasticity, neuronal excitability, neuronal differentiation during early development, and learning and memory

a(MESH:"Cerebral Cortex") association p(HGNC:CHRM1) View Subject | View Object

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a(MESH:"Corpus Striatum") association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

a(MESH:Hippocampus) association p(HGNC:CHRM1) View Subject | View Object

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a(MESH:Thalamus) association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

bp(GO:"neuron differentiation") association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

bp(GO:"neuronal signal transduction") association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

bp(GO:"regulation of synaptic plasticity") association p(HGNC:CHRM1) View Subject | View Object

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bp(GO:learning) association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

bp(GO:memory) association p(HGNC:CHRM1) View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association a(MESH:"Cerebral Cortex") View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association a(MESH:"Corpus Striatum") View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association a(MESH:Thalamus) View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association bp(GO:"regulation of synaptic plasticity") View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association bp(GO:learning) View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association bp(GO:memory) View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association bp(GO:"neuronal signal transduction") View Subject | View Object

Appears in Networks:

p(HGNC:CHRM1) association bp(GO:"neuron differentiation") View Subject | View Object

Appears in Networks:

p(MGI:Chrm1) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:

p(MGI:Chrm1) increases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:

Evidence 56e0b935d4
JSON

M5 mAChR is predominantly distributed in the pars compacta of the substantia nigra, a structure that provides dopaminergic innervation to the striatum, and in the ventral tegmental area, a structure providing dopaminergic innervation to the nucleus accumbens and other limbic areas[26, 57]. These areas are well known to play a critical role in the rewarding effects of several drugs of abuse. M5 mAChR-knockout mice are less sensitive to addictive drugs such as morphine and cocaine[58].

a(MESH:"Pars Compacta") association p(HGNC:CHRM5) View Subject | View Object

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p(HGNC:CHRM5) association a(MESH:"Pars Compacta") View Subject | View Object

Appears in Networks:

p(HGNC:CHRM5) increases bp(GO:"response to drug") View Subject | View Object

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p(HGNC:CHRM5) increases act(a(CHEBI:morphine)) View Subject | View Object

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p(HGNC:CHRM5) increases act(a(CHEBI:cocaine)) View Subject | View Object

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Evidence 24e72d0f14
JSON

Similarly, the M1 agonist WAY-132983 at a low dose improves cognitive status in animal models but at a high dose causes side-effects such as salivation and hypothermia[102, 112].

a(MESH:"WAY 132983") increases bp(GO:cognition) View Subject | View Object

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a(MESH:"WAY 132983") increases path(MESH:Salivation) View Subject | View Object

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a(MESH:"WAY 132983") increases path(MESH:Hypothermia) View Subject | View Object

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Evidence 5fb92a44d2
JSON

Another M1 mAChR-selective agonist, talsaclidine, enhances nonamyloidogenic processing of APP, resulting in increased sAPPalpha release from both a transfected human astrocytoma cell line and rat brain slices in a dose-dependent manner, as well as significantly decreasing CSF Abeta in AD patients[111]. However, talsaclidine at high doses had several side-effects such as sweating and salivation

a(MESH:"talsaclidine fumarate") increases a(HBP:"sAPP-alpha") View Subject | View Object

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a(MESH:"talsaclidine fumarate") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
MeSH
Cerebrospinal Fluid

a(MESH:"talsaclidine fumarate") increases path(MESH:Sweating) View Subject | View Object

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a(MESH:"talsaclidine fumarate") increases path(MESH:Salivation) View Subject | View Object

Appears in Networks:

Evidence ed490240c1
JSON

M2 mAChR is expressed throughout the brain, including the hippocampus and neocortex, and is abundant in non-cholinergic neurons that project to these areas. In the caudate-putamen, M2 mAChR acts as an inhibitory modulator on dopaminergic terminals[46-48].

p(HGNC:CHRM2) association a(MESH:Hippocampus) View Subject | View Object

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p(HGNC:CHRM2) association a(MESH:Neocortex) View Subject | View Object

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a(MESH:Hippocampus) association p(HGNC:CHRM2) View Subject | View Object

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a(MESH:Neocortex) association p(HGNC:CHRM2) View Subject | View Object

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p(HGNC:CHRM2) decreases act(a(CHEBI:dopamine)) View Subject | View Object

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Annotations
MeSH
Neostriatum

Evidence 634035372a
JSON

M3 mAChR is expressed at a relatively high level in the hypothalamus, but is also found in many other regions including the hippocampus[47]. Mice lacking M3 mAChR appear hypophagic and lean, suggesting a general function of M2 mAChR in regulating food intake[50].

a(MESH:Hippocampus) association p(HGNC:CHRM3) View Subject | View Object

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a(MESH:Hypothalamus) association p(HGNC:CHRM3) View Subject | View Object

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p(HGNC:CHRM3) association a(MESH:Hypothalamus) View Subject | View Object

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p(HGNC:CHRM3) association a(MESH:Hippocampus) View Subject | View Object

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p(MGI:Chrm3) regulates bp(GO:"response to food") View Subject | View Object

Appears in Networks:

Evidence ad4ebbcea3
JSON

Some studies suggest that M1 mAChR stimulation also leads to activation of ERK1/2, which can modulate alpha-secretase activity and APP processing[67, 73],

bp(GO:"ERK1 and ERK2 cascade") regulates act(p(HGNC:ADAM10)) View Subject | View Object

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bp(GO:"ERK1 and ERK2 cascade") regulates bp(HBP:"APP processing") View Subject | View Object

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act(p(HGNC:CHRM1)) increases bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

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Evidence 1ddb026e6b
JSON

In addition to inhibiting Abeta generation, activation of M1 mAChR counteracts Abeta-induced neurotoxicity through the Wnt signaling pathway, as Abeta impairs the Wnt pathway and M1 mAChR stimulation inactivates GSK-3beta via PKC activation, stabilizes beta-catenin, and induces the expression of Wnt-targeting genes engrailed and cyclin-D1 for neuron survival

bp(GO:"Wnt signaling pathway") decreases bp(HBP:neurotoxicity) View Subject | View Object

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act(p(HGNC:CHRM1)) increases act(p(FPLX:PKC)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) decreases act(p(HGNC:GSK3B)) View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) increases bp(HBP:neurotoxicity) View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) increases bp(GO:"Wnt signaling pathway") View Subject | View Object

Appears in Networks:

act(p(FPLX:PKC)) decreases act(p(HGNC:GSK3B)) View Subject | View Object

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Evidence 378d40ff22
JSON

Recent evidence indicates that cholinergic hypofunction is closely linked to Abeta and tau pathologies[20]. As a major receptor group for ACh, mAChRs have also been implicated in the pathophysiology of AD.

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:"synaptic transmission, cholinergic") association path(MESH:"Plaque, Amyloid") View Subject | View Object

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bp(GO:"synaptic transmission, cholinergic") association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Appears in Networks:

path(MESH:"Neurofibrillary Tangles") association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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path(MESH:"Plaque, Amyloid") association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Appears in Networks:

Evidence dd7c69c610
JSON

mAChRs are seven-transmembrane G-proteincoupled receptors. Upon binding to the endogenous neurotransmitter ACh, mAChRs couple to G proteins to transduct signals

complex(a(CHEBI:acetylcholine), p(FPLX:"G_protein"), p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic")) increases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

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Evidence 92a071c460
JSON

At the cellular level, M1 mAChR is highly expressed in striatonigral, striatopallidal, and glutamatergic pyramidal neurons, especially in extrasynaptic regions. This localization of M1 mAChR is consistent with the cholinergic modulation of glutamatergic neurotransmission

p(HGNC:CHRM1) regulates bp(GO:"synaptic transmission, glutamatergic") View Subject | View Object

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Annotations
Cell Ontology (CL)
glutamatergic neuron

Evidence 5f66cffee9
JSON

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface

act(p(HGNC:CHRM1)) increases a(HBP:"sAPP-alpha") View Subject | View Object

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act(p(HGNC:CHRM1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

act(p(HGNC:CHRM1)) increases act(p(FPLX:PKC)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PKC)) increases act(p(HGNC:ADAM10)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PKC)) increases tloc(p(HGNC:APP), fromLoc(GO:"Golgi apparatus"), toLoc(GO:"cell surface")) View Subject | View Object

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Evidence a7ee680dc0
JSON

though there are contradictory findings showing that the alpha-secretase-mediated APP processing via M1 mAChR stimulation is not modulated by the ERK1/MEK cascade[71]. On the other hand, loss of M1 mAChR increases amyloidogenic APP processing in neurons and promotes brain Abeta plaque pathology in a mouse model of AD

act(p(HGNC:CHRM1)) causesNoChange bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

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act(p(MGI:Chrm1)) decreases bp(HBP:"APP processing") View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

act(p(MGI:Chrm1)) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence b57344f2be
JSON

Activation of M1 mAChR also protects against apoptotic factors in human neuroblastoma SH-SY5Y cells, such as DNA damage, oxidative stress, caspase activation, and mitochondrial impairment[83]. In addition, apoptosis induced by serum deprivation is blocked by M1 mAChR activation in a phosphoinositide 3-kinase- and MAPK/ERKindependent manner

act(p(HGNC:CHRM1)) decreases bp(GO:"cell death") View Subject | View Object

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act(p(HGNC:CHRM1)) decreases path(MESH:"DNA Damage") View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

act(p(HGNC:CHRM1)) decreases path(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

act(p(HGNC:CHRM1)) decreases act(p(HGNCGENEFAMILY:Caspases)) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 340129174f
JSON

So far, five mAChR subtypes (M1– M5) have been identified and are divided into two categories based on the manner of signal transduction: M1, M3, and M5 subtypes preferentially interact with the Gq/11 family of G proteins, activating phospholipase C and mobilizing intracellular calcium, while M2 and M4 subtypes couple to the Go/i family, inhibiting adenylate cyclases and reducing intracellular cAMP levels

complex(p(HGNC:CHRM1), p(HGNC:GNA11)) increases act(p(FPLX:PLC)) View Subject | View Object

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complex(p(HGNC:CHRM1), p(HGNC:GNA11)) increases bp(GO:"calcium ion transport") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM2), p(HGNC:GNAO1)) decreases p(HGNCGENEFAMILY:"Adenylate cyclases") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM2), p(HGNC:GNAO1)) decreases a(CHEBI:"3',5'-cyclic AMP") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM3), p(HGNC:GNA11)) increases act(p(FPLX:PLC)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM3), p(HGNC:GNA11)) increases bp(GO:"calcium ion transport") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM4), p(HGNC:GNAO1)) decreases p(HGNCGENEFAMILY:"Adenylate cyclases") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM4), p(HGNC:GNAO1)) decreases a(CHEBI:"3',5'-cyclic AMP") View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM5), p(HGNC:GNA11)) increases act(p(FPLX:PLC)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRM5), p(HGNC:GNA11)) increases bp(GO:"calcium ion transport") View Subject | View Object

Appears in Networks:

Evidence 1d67b6f4fb
JSON

Mice deficient in M2 mAChR also show a striking reduction in muscarinic-dependent antinociceptive responses[49], suggesting a general antinociceptive effect.

p(MGI:Chrm2) decreases path(MESH:"Nociceptive Pain") View Subject | View Object

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Evidence bdc864639d
JSON

Consistently, mice with conditional knockout of M3 mAChR in the brain exhibit a dwarf phenotype. They also exhibit hypoplasia of the anterior pituitary gland and significantly decreased hormones including pituitary prolactin and growth hormone[51]. These fi ndings indicate that M3 mAChR plays a critical role in promoting body growth.

p(MGI:Chrm3) increases bp(GO:"pituitary gland development") View Subject | View Object

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p(MGI:Chrm3) increases p(MGI:Prl) View Subject | View Object

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p(MGI:Chrm3) increases p(MGI:Gh) View Subject | View Object

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p(MGI:Chrm3) increases bp(GO:"multicellular organism growth") View Subject | View Object

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Evidence 6b2f0f6df1
JSON

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy

path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

path(MESH:"Neurofibrillary Tangles") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Plaque, Amyloid") association path(MESH:"Alzheimer Disease") View Subject | View Object

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.