RGD Reference Report - Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin. - Rat Genome Database

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Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin.

Authors: Toulme, E  Soto, F  Garret, M  Boue-Grabot, E 
Citation: Toulme E, etal., Mol Pharmacol. 2006 Feb;69(2):576-87. Epub 2005 Nov 10.
RGD ID: 1642691
Pubmed: PMID:16282518   (View Abstract at PubMed)
DOI: DOI:10.1124/mol.105.018812   (Journal Full-text)

Although P2X receptors within the central nervous system mediate excitatory ATP synaptic transmission, the identity of central ATP-gated channels has not yet been elucidated. P2X(4), the most widely expressed subunit in the brain, was previously shown to undergo clathrin-dependent constitutive internalization by direct interaction between activator protein (AP)2 adaptors and a tyrosine-based sorting signal specifically present in the cytosolic C-terminal tail of mammalian P2X(4) sequences. In this study, we first used internalization-deficient P2X(4) receptor mutants to show that suppression of the endocytosis motif significantly increased the apparent sensitivity to ATP and the ionic permeability of P2X(4) channels. These unique properties, observed at low channel density, suggest that interactions with AP2 complexes may modulate the function of P2X(4) receptors. In addition, ivermectin, an allosteric modulator of several receptor channels, including mammalian P2X(4), did not potentiate the maximal current of internalization-deficient rat or human P2X(4) receptors. We demonstrated that binding of ivermectin onto wild-type P2X(4) channels increased the fraction of plasma membrane P2X(4) receptors, whereas surface expression of internalization-deficient P2X(4) receptors remained unchanged. Disruption of the clathrin-mediated endocytosis with the dominant-negative mutants Eps15 or AP-50 abolished the ivermectin potentiation of wild-type P2X(4) channel currents. Likewise, ivermectin increased the membrane fraction of nicotinic alpha7 acetylcholine (nalpha7ACh) receptors and the potentiation of acetylcholine current by ivermectin was suppressed when the same dominant-negative mutants were expressed. These data showed that potentiation by ivermectin of both P2X(4) and nalpha7ACh receptors was primarily caused by an increase in the number of cell surface receptors resulting from a mechanism dependent on clathrin/AP2-mediated endocytosis.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CHRNA7Humanivermectin increases expression ISOChrna7 (Rattus norvegicus)ivermectin increases expression of Chrna7 on membrane surface of oocytes expressing rat proteinRGD 
Chrna7Rativermectin increases expression EXP ivermectin increases expression of Chrna7 on membrane surface of oocytes expressing rat proteinRGD 
Chrna7Mouseivermectin increases expression ISOChrna7 (Rattus norvegicus)ivermectin increases expression of Chrna7 on membrane surface of oocytes expressing rat proteinRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
P2rx4Ratcellular response to ATP enablesIMP  RGD 
P2rx4Ratclathrin-dependent endocytosis enablesIMP  RGD 
P2rx4Ratinorganic cation transmembrane transport  IDA  RGD 
Chrna7Ratmonoatomic ion transmembrane transport  IDA  RGD 
Chrna7Ratregulation of response to drug involved_inIDA ivermectin CHEBI:6078RGD 
P2rx4Ratregulation of response to drug enablesIMP ivermectin CHEBI:6078RGD 
Chrna7Ratresponse to acetylcholine involved_inIDA ivermectin CHEBI:6078RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
P2rx4Ratextracellularly ATP-gated monoatomic cation channel activity enablesIDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Chrna7  (cholinergic receptor nicotinic alpha 7 subunit)
P2rx4  (purinergic receptor P2X 4)

Genes (Mus musculus)
Chrna7  (cholinergic receptor, nicotinic, alpha polypeptide 7)

Genes (Homo sapiens)
CHRNA7  (cholinergic receptor nicotinic alpha 7 subunit)


Additional Information