Calcineurin inhibitor protein (CAIN) attenuates group I metabotropic glutamate receptor endocytosis and signaling

Lucimar T. Ferreira, Lianne B. Dale, Fabiola M. Ribeiro, Andy Babwah, Macarena Pampillo, Stephen S G Ferguson

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Group I metabotropic glutamate receptors (mGluRs) are coupled via phospholipase Cβ to the hydrolysis of phosphoinositides and function to modulate neuronal excitability and synaptic transmission at glutamatergic synapses. The desensitization of Group I mGluR signaling is thought to be mediated primarily via second messenger-dependent protein kinases and G protein-coupled receptor kinases. We show here that both mGluR1 and mGluR5 interact with the calcineurin inhibitor protein (CAIN). CAIN is co-immunoprecipitated in a complex with Group I mGluRs from both HEK 293 cells and mouse cortical brain lysates. Purified CAIN and its C-terminal domain specifically interact with glutathione S-transferase fusion proteins corresponding to the second intracellular loop and the distal C-terminal tail domains of mGluR1. The interaction of CAIN with mGluR1 could also be blocked using a Tat-tagged peptide corresponding to the mGluR1 second intracellular loop domain. Overexpression of full-length CAIN attenuates the agonist-stimulated endocytosis of both mGluR1a and mGluR5a in HEK 293 cells, but expression of the CAIN C-terminal domain does not alter mGluR5a internalization. In contrast, overexpression of either full-length CAIN or the CAIN C-terminal domain impairs agonist-stimulated inositol phosphate formation in HEK 293 cells expressing mGluR1a. This CAIN-mediated antagonism of mGluR1a signaling appears to involve the disruption of receptor-Gαq/11 complexes. Taken together, these observations suggest that the association of CAIN with intracellular domains involved in mGluR/G protein coupling provides an additional mechanism by which Group I mGluR endocytosis and signaling are regulated.

Original languageEnglish (US)
Pages (from-to)28986-28994
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number42
DOIs
StatePublished - Oct 16 2009

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Metabotropic Glutamate Receptors
Endocytosis
Proteins
HEK293 Cells
Protein C
G-Protein-Coupled Receptor Kinases
Calcineurin Inhibitors
Cyclic GMP-Dependent Protein Kinases
Inositol Phosphates
Type C Phospholipases
Second Messenger Systems
Phosphatidylinositols
metabotropic glutamate receptor type 1
Glutathione Transferase
GTP-Binding Proteins
Synaptic Transmission
Synapses
Tail
Hydrolysis
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Cite this

Ferreira, Lucimar T. ; Dale, Lianne B. ; Ribeiro, Fabiola M. ; Babwah, Andy ; Pampillo, Macarena ; Ferguson, Stephen S G. / Calcineurin inhibitor protein (CAIN) attenuates group I metabotropic glutamate receptor endocytosis and signaling. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 42. pp. 28986-28994.
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Calcineurin inhibitor protein (CAIN) attenuates group I metabotropic glutamate receptor endocytosis and signaling. / Ferreira, Lucimar T.; Dale, Lianne B.; Ribeiro, Fabiola M.; Babwah, Andy; Pampillo, Macarena; Ferguson, Stephen S G.

In: Journal of Biological Chemistry, Vol. 284, No. 42, 16.10.2009, p. 28986-28994.

Research output: Contribution to journalArticle

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AU - Dale, Lianne B.

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