Activated CaMKIIα Binds to the mGlu5 Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.
Mol Pharmacol
; 94(6): 1352-1362, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-30282777
ABSTRACT
Ca2+/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu5) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu5 is present in CaMKIIα complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu5a directly interacts with purified Thr286-autophosphorylated (activated) CaMKIIα However, the binding of CaMKIIα to this CTD fragment is reduced by the addition of excess Ca2+/calmodulin or by additional CaMKIIα autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKIIα is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu5a-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKIIα with full-length mGlu5a expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKIIα with mGlu5a in heterologous cells. First, cell-surface biotinylation studies showed that CaMKIIα increases the surface expression of mGlu5a Second, using Ca2+ fluorimetry and single-cell Ca2+ imaging, we found that CaMKIIα reduces the initial peak of mGlu5a-mediated Ca2+ mobilization by about 25% while doubling the relative duration of the Ca2+ signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cálcio
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
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Receptor de Glutamato Metabotrópico 5
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article