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PubMed: 22040696

Title
Chaperoning α7 neuronal nicotinic acetylcholine receptors.
Journal
Biochimica et biophysica acta
Volume
1818
Issue
None
Pages
718-29
Date
2012-03-01
Authors
Barrantes FJ | Vallés AS

Evidence 84d4391e71
JSON

AChRs have been linked to many neurodegenerative disorders [13,47–60].

p(HGNC:CHRNA7) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Neurodegenerative Diseases") association p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:

Evidence 2319733475
JSON

BDNF can also influence the level of α7 AChRs subunits (Fig. 4) in the hippocampus and other brain regions [160,164,165].

p(HGNC:CHRNA7) association p(HGNC:BDNF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Hippocampus

p(HGNC:BDNF) association p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Hippocampus

Evidence 5e9ea1d65c
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Since α7 AChRs are highly permeable to calcium [198] and increased calcium permeability is required for neuronal migration [199], neurons with less α7 AChRs would fail to migrate to their correct destinations [200] and be activated by acetylcholine.

tloc(a(CHEBI:"calcium(2+)"), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:Cytoplasm)) increases bp(GO:"neuron migration") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Hippocampus

p(HGNC:CHRNA7) increases tloc(a(CHEBI:"calcium(2+)"), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:Cytoplasm)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Hippocampus

Evidence 63a286a30f
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Furthermore, nicotinic stimulation rapidly induced SNARE-dependent vesicular endocytosis accompanied by receptor internalization [166]. However, the number of surface α7 AChRs was not modified since a SNARE-dependent pro- cess also recruited receptors to the cell surface from internal pools (Fig. 5).

a(CHEBI:nicotine) increases act(a(MESH:"SNARE Proteins")) View Subject | View Object

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act(a(MESH:"SNARE Proteins")) increases tloc(p(HGNC:CHRNA7), fromLoc(GO:"cell surface"), toLoc(GO:endosome)) View Subject | View Object

Appears in Networks:

act(a(MESH:"SNARE Proteins")) causesNoChange surf(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence 650f1c1dd6
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Recent studies have also demonstrated the importance of the phos- phatidylinositol 3-kinase (PI3K) pathway downstream of AChRs in pro- tecting neurons from death and up-regulating these receptors [148].

bp(GO:"phosphatidylinositol 3-kinase signaling") decreases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

bp(GO:"phosphatidylinositol 3-kinase signaling") increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

Evidence 35fbeb15f9
JSON

During acute in- flammatory processes α7 AChRs attenuate renal failure induced by ische- mia/reperfusion by inhibiting pro-inflammatory cytokine expression, and subsequently decreasing cell apoptosis [180,201].

bp(GO:"response to ischemia") increases path(MESH:"Renal Insufficiency") View Subject | View Object

Appears in Networks:

p(HGNC:CHRNA7) decreases path(MESH:"Renal Insufficiency") View Subject | View Object

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Annotations
MeSH
Inflammation

p(HGNC:CHRNA7) decreases bp(GO:"cytokine production") View Subject | View Object

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Annotations
MeSH
Inflammation

p(HGNC:CHRNA7) decreases bp(GO:"apoptotic process") View Subject | View Object

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Annotations
MeSH
Inflammation

path(MESH:Inflammation) increases path(MESH:"Renal Insufficiency") View Subject | View Object

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Evidence a7aee4decd
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One of the salient events at early stages of this disease (usually pre- clinical) is the impairment in hippocampus-based episodic memory which can be improved by enhancement of cholinergic transmission [191].

bp(GO:"synaptic transmission, cholinergic") increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

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

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 8b26589a51
JSON

Regulation of receptor subunits by the proteasome, the large pro- tein complex that proteolytically degrades unneeded proteins, has also been demonstrated [113,114].

complex(GO:"proteasome complex") regulates p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

Evidence 6a89be9029
JSON

Furthermore, the proteasome in- directly regulates synaptic transmission mediated by AChRs via regu- lation of RIC-3 [113].

complex(GO:"proteasome complex") increases bp(GO:"modulation of chemical synaptic transmission") View Subject | View Object

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complex(GO:"proteasome complex") regulates p(HGNC:RIC3) View Subject | View Object

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Evidence fde4dc806d
JSON

Another important event that associates well with the Alzheimer disease pathology is the aggregation of the β-amyloid peptide [53]. This peptide interacts with α7 AChRs and has been reported to affect the nor- mal functioning of the latter, causing reduced neuronal survival [146,192–194].

complex(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNA7)) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

complex(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNA7)) decreases act(p(HGNC:CHRNA7)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") increases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 35d07ef189
JSON

α7 AChRs can act at the presynaptic, postsynaptic or perisynaptic levels to facilitate the liberation of neurotransmitters, mediate synaptic transmission, or modulate the connections of different neurons by activating diverse second messenger routes [1,19,23–31].

p(HGNC:CHRNA7) increases bp(GO:"neurotransmitter secretion") View Subject | View Object

Appears in Networks:

p(HGNC:CHRNA7) regulates bp(GO:"chemical synaptic transmission") View Subject | View Object

Appears in Networks:

p(HGNC:CHRNA7) regulates bp(GO:"neuron-neuron synaptic transmission") View Subject | View Object

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Evidence 3f43056b45
JSON

Additionally, SNARE-dependent trafficking was required for α7 AChRs to be capable of activating the transcription factor cAMP response element-binding protein and attendant gene ex- pression when challenged.

tloc(p(HGNC:CHRNA7), fromLoc(GO:"cell surface"), toLoc(GO:endosome)) increases act(p(HGNC:CREB1), ma(tscript)) View Subject | View Object

Appears in Networks:

Evidence bd6a8e1958
JSON

Reduction of α7 AChRs in the CNS is linked with Alzheimer dis- ease, which has been shown to lead to neuronal loss [53,188–190].

p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Central Nervous System

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

Appears in Networks:
Annotations
MeSH
Central Nervous System

Evidence 1857487bf4
JSON

Decreased expression of α7 AChR has also been associated with schizophrenia [51,195–197].

p(HGNC:CHRNA7) negativeCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:Schizophrenia) negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 8a2d005e42
JSON

In adrenal medulla chromaffin cells the tyrosine kinases c-SRC and FYN associate with the α3β4 receptor and are involved in the cholinergic stimulation of catecholamine secretion [141,144,145].

complex(p(FPLX:CHRN), p(HGNC:FYN)) increases bp(GO:"catecholamine secretion") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Medulla

complex(p(FPLX:CHRN), p(FPLX:SRC)) increases bp(GO:"catecholamine secretion") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Medulla

Evidence 39534efc25
JSON

Although the mechanisms that regulate phosphorylation of AChRs are still essen- tially unknown, protein tyrosine phosphorylation by the SFKs has been shown to affect peripheral AChRs in various ways, depending on the tis- sue, subunit type and functional role of the receptors involved.

act(p(FPLX:SRC), ma(kin)) increases p(FPLX:CHRN, pmod(Ph, Tyr)) View Subject | View Object

Appears in Networks:

Evidence 11ada65525
JSON

In Torpedo electric organ, phosphorylation of AChRs by SFKs causes subtle changes in desensitization kinetics but not in I max , the maximal current flowing through the receptor channel [141–143].

act(p(FPLX:SRC), ma(kin)) increases p(FPLX:CHRN, pmod(Ph, Tyr)) View Subject | View Object

Appears in Networks:

p(FPLX:CHRN, pmod(Ph, Tyr)) decreases act(p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:

Evidence bcc8b68082
JSON

More re- cently, the transmembrane protein resistant to inhibitors of cholines- terase (RIC-3), originally identified in Caenorhabditis elegans, has been classed as a much more selective chaperone of the AChR [71,107–112].

act(p(HGNC:RIC3), ma(chap)) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

Evidence 2f16547f3d
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Co-expression with RIC-3 was shown to be required for AChR ac- tivity in C. elegans body muscles and for enhanced AChR activity in Xenopus oocytes [110,112].

p(HGNC:RIC3) increases act(p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:

Evidence b8bd304e6a
JSON

Interestingly, levels of RIC-3 mRNA are elevat- ed in postmortem brains of individuals with bipolar disorder and schizophrenia [181], and a link has been suggested between defi- cient RIC-3 mediated chaperoning of an AChR subunit and individ- uals with bipolar disorder and psychotic symptoms [181].

act(p(HGNC:RIC3), ma(chap)) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(p(HGNC:RIC3), ma(chap)) negativeCorrelation path(MESH:"Bipolar Disorder") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

act(p(HGNC:RIC3), ma(chap)) negativeCorrelation path(MESH:"Psychotic Disorders") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Bipolar Disorder") positiveCorrelation r(HGNC:RIC3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Bipolar Disorder") negativeCorrelation act(p(HGNC:RIC3), ma(chap)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Psychotic Disorders") negativeCorrelation act(p(HGNC:RIC3), ma(chap)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Schizophrenia) positiveCorrelation r(HGNC:RIC3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

r(HGNC:RIC3) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

r(HGNC:RIC3) positiveCorrelation path(MESH:"Bipolar Disorder") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 0c5a35f2c7
JSON

In C. elegans, RIC-3 is necessary for synaptic transmission mediated by neuronal AChRs but not by other LGICs [71,77,109].

p(HGNC:RIC3) increases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Appears in Networks:

Evidence 709048b0cf
JSON

In contrast, RIC-3 caused a marked inhibition of functional responses with hetero- meric α3β4 and α4β2 AChRs in Xenopus oocytes [109].

p(HGNC:RIC3) decreases act(complex(p(HGNC:CHRNA3), p(HGNC:CHRNB4))) View Subject | View Object

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p(HGNC:RIC3) decreases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) View Subject | View Object

Appears in Networks:

Evidence 779ef16698
JSON

Osman et al. [122] find that RIC-3 expression increases the total amount of α9 AChR in CL4 cells, supporting the view that RIC-3 regulates AChR trafficking by increasing the number of mature or correctly folded receptor subunits reaching the cell surface.

p(HGNC:RIC3) increases p(HGNC:CHRNA9) View Subject | View Object

Appears in Networks:

Evidence e16480057d
JSON

It is noteworthy that RIC-3 has been shown to increase α7 AChR heterologous expression both in X. laevis oocytes and in HEK-293, CHO and SHE-P1 mammalian cell lines [66,71,77,107–112,119,125].

p(HGNC:RIC3) increases p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:

Evidence 90bbfd1ecc
JSON

Specifically, it has been shown that upon stimulation, α7 AChR activates PI3K via direct association with non-receptor type tyrosine kinase FYN and Janus-activated kinase 2 (JAK2), promoting the survival of neuronal cells (Fig. 3).

complex(p(HGNC:CHRNA7), p(HGNC:FYN)) increases act(p(FPLX:PI3K)) View Subject | View Object

Appears in Networks:

complex(p(HGNC:CHRNA7), p(HGNC:JAK2)) increases act(p(FPLX:PI3K)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PI3K)) decreases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:

Evidence f3fc8ccd80
JSON

Reduced expression of the lat- ter protein has been shown to be detrimental to AChR function in C. elegans [113] (See Fig. 2).

p(UNIPROT:P34371) increases act(p(FPLX:CHRN)) View Subject | View Object

Appears in Networks:

Evidence 980eecdd38
JSON

Co- expression of RIC-3 with the 5-HT 3 receptor in X. laevis oocytes totally abolishes 5-HT 3 surface expression [108,109].

composite(p(HGNC:HTR3A), p(HGNC:RIC3)) decreases surf(p(HGNC:HTR3A)) View Subject | View Object

Appears in Networks:

Evidence 0f6f969a67
JSON

There is evidence that AChR folding, assembly and trafficking are influenced by several chaperone proteins, such as the 14-3-3 protein [92,93], BiP [94–96] or calnexin [97–99].

p(FPLX:"p14_3_3") increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

p(HGNC:CANX) increases p(FPLX:CHRN) View Subject | View Object

Appears in Networks:

p(HGNC:HSPA5) increases p(FPLX:CHRN) View Subject | View Object

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Evidence a18f18b784
JSON

Additionally, the pro- lyl isomerase enzyme cyclophilin has been shown to be necessary for efficient folding of the α7 subunit in Xenopus oocytes [85–88].

p(FPLX:Cyclophilin) increases p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:

Evidence 5714b0808a
JSON

BDNF regulates development of neuronal structures both in the pe- ripheral and central nervous systems [150–155].

p(HGNC:BDNF) regulates bp(GO:"peripheral nervous system development") View Subject | View Object

Appears in Networks:

p(HGNC:BDNF) regulates bp(GO:"central nervous system development") View Subject | View Object

Appears in Networks:

Evidence b031bf44ae
JSON

It has acute effects on the synapse, serving as an activity-dependent regulator of synaptic plas- ticity and participating in rapid synaptic transmission [150,151,156–159], in the maturation of GABAergic signaling and in the stabilization of newly formed synapses [151,160–163].

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

Appears in Networks:

p(HGNC:BDNF) increases bp(GO:"spontaneous synaptic transmission") View Subject | View Object

Appears in Networks:

p(HGNC:BDNF) increases bp(GO:"synaptic transmission, GABAergic") View Subject | View Object

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p(HGNC:BDNF) increases bp(GO:"maintenance of synapse structure") View Subject | View Object

Appears in Networks:

Evidence 091d60373d
JSON

Recent studies using dissociated rat hippocampal neurons in culture demonstrated that BDNF increases both surface and internal α7 AChRs pools.

p(HGNC:BDNF) increases p(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:

p(HGNC:BDNF) increases surf(p(HGNC:CHRNA7)) View Subject | View Object

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Evidence 45e943e621
JSON

Tyrosine phosphorylation of α7 AChR was found to negatively regulate receptor activity in neuroblastoma cells, hippo- campal CA1 interneurons, and supraoptic magnocellular neurons, whereas de-phosphorylation of α7 AChR was found to potentiate ACh-evoked currents in these cells.

p(HGNC:CHRNA7, pmod(Ph, Tyr)) decreases act(p(HGNC:CHRNA7)) View Subject | View Object

Appears in Networks:

Evidence cfb799f0ae
JSON

A recent study showed that mutation of amino acids from this region (leucines 335, 336 or 343) to alanine reduced cell-surface expression of α7 AChRs [173].

p(HGNC:CHRNA7, var("p.Leu335Ala")) decreases surf(p(HGNC:CHRNA7)) View Subject | View Object

Appears in Networks:

p(HGNC:CHRNA7, var("p.Leu336Ala")) decreases surf(p(HGNC:CHRNA7)) View Subject | View Object

Appears in Networks:

p(HGNC:CHRNA7, var("p.Leu343Ala")) decreases surf(p(HGNC:CHRNA7)) View Subject | View Object

Appears in Networks:

Evidence f3fa749f7e
JSON

Rapsyn is essential for AChR clustering in muscle [100] and has also been detected in non-muscle cells, including neurons of the ciliary ganglia [101,102], fibroblasts [103], myocardial cells, and Leydig cells [104].

p(HGNC:RAPSN) increases bp(GO:"skeletal muscle acetylcholine-gated channel clustering") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Muscles

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