RGD Reference Report - PMCA2 via PSD-95 controls calcium signaling by alpha7-containing nicotinic acetylcholine receptors on aspiny interneurons. - Rat Genome Database

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PMCA2 via PSD-95 controls calcium signaling by alpha7-containing nicotinic acetylcholine receptors on aspiny interneurons.

Authors: Gomez-Varela, D  Schmidt, M  Schoellerman, J  Peters, EC  Berg, DK 
Citation: Gomez-Varela D, etal., J Neurosci. 2012 May 16;32(20):6894-905. doi: 10.1523/JNEUROSCI.5972-11.2012.
RGD ID: 7205692
Pubmed: PMID:22593058   (View Abstract at PubMed)
PMCID: PMC3369694   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.5972-11.2012   (Journal Full-text)

Local control of calcium concentration within neurons is critical for signaling and regulation of synaptic communication in neural circuits. How local control can be achieved in the absence of physical compartmentalization is poorly understood. Challenging examples are provided by nicotinic acetylcholine receptors that contain alpha7 nicotinic receptor subunits (alpha7-nAChRs). These receptors are highly permeable to calcium and are concentrated on aspiny dendrites of interneurons, which lack obvious physical compartments for constraining calcium diffusion. Using functional proteomics on rat brain, we show that alpha7-nAChRs are associated with plasma membrane calcium-ATPase pump isoform 2 (PMCA2). Analysis of alpha7-nAChR function in hippocampal interneurons in culture shows that PMCA2 activity limits the duration of calcium elevations produced by the receptors. Unexpectedly, PMCA2 inhibition triggers rapid calcium-dependent loss of alpha7-nAChR clusters. This extreme regulatory response is mediated by CaMKII, involves proteasome activity, depends on the second intracellular loop of alpha7-nAChR subunits, and is specific in that it does not alter two other classes of calcium-permeable ionotropic receptors on the same neurons. A critical link is provided by the scaffold protein PSD-95 (postsynaptic density-95), which is associated with alpha7-nAChRs and constrains their mobility as revealed by single-particle tracking on neurons. The PSD-95 link is required for PMCA2-mediated removal of alpha7-nAChR clusters. This three-component combination of PMCA2, PSD-95, and alpha7-nAChR offers a novel mechanism for tight control of calcium dynamics in neurons.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
acetylcholine receptor binding  IDA 7205692 RGD 
ATPase binding  IDA 7205692 RGD 
scaffold protein binding  IDA 7205692 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Chrna7  (cholinergic receptor nicotinic alpha 7 subunit)
Dlg4  (discs large MAGUK scaffold protein 4)

Objects referenced in this article
Gene Atp2b2 ATPase plasma membrane Ca2+ transporting 2 Rattus norvegicus

Additional Information