The Role of Ca2+/Calmodulin Dependent Protein Kinase II Alpha in Group 1 Metabotropic Glutamate Receptor Endocytosis and Signalling

Author

Stephanie C. Kulhawy, The University of Western OntarioFollow

Degree

Master of Science

Program

Physiology

Supervisor

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 Gα_q/11 and releases Ca²⁺ from the endoplasmic reticulum. Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) can be activated by Gα_q/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.

Recommended Citation

Kulhawy, Stephanie C., "The Role of Ca2+/Calmodulin Dependent Protein Kinase II Alpha in Group 1 Metabotropic Glutamate Receptor Endocytosis and Signalling" (2012). Electronic Thesis and Dissertation Repository. 1051.
https://ir.lib.uwo.ca/etd/1051