Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor(s)

Dr. Stephen Ferguson

Abstract

Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) are G-protein coupled receptors (GPCRs) activated by glutamate. mGluR1/5 couples to Gαq/11 and releases Ca2+ from the endoplasmic reticulum. Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) can be activated by Gαq/11-mediated Ca2+ release through binding of Ca2+/calmodulin. Results from a proteomic screen identified CaMKII as a novel mGluR-interacting protein. Therefore, we hypothesized that CaMKIIα associates with group 1 mGluRs and this association alters mGluR1/5 signalling and internalization. Firstly, we demonstrated the novel association between CaMKIIα and mGluR1/5 by co-immunoprecipitation of transiently transfected proteins in HEK293 cells and of endogenous proteins in mouse hippocampal tissue. Next, we showed that the second intracellular loop of the mGluR1a receptor is sufficient for this association. Furthermore, CaMKIIα significantly enhances agonist-induced internalization of group 1 mGluRs. Yet, it does not appear that CaMKIIα plays a significant role in receptor signalling by either ERK1/2 phosphorylation or inositol phosphosphate formation. Both CaMKIIα and mGluR1/5 play an important role in memory, learning and synaptic transmission. Understanding how these two players work together could provide a mechanism for reducing excitotoxicity through desensitization of mGluR1/5 by CaMKIIα.


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