Featured Grad Paper: Jessica Esseltine

Jessica Esseltine


Rab8 modulates metabotropic glutamate receptor subtype 1 intracellular trafficking and signaling in a protein kinase C-dependent manner.


Esseltine JL, Ribeiro FM, Ferguson SS.
J Neurosci. 2012 Nov 21;32(47):16933-42. doi: 10.1523/JNEUROSCI.0625-12.2012.

Abstract
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are activated by glutamate, the primary excitatory neurotransmitter in the CNS. Alterations in glutamate receptor signaling are implicated in neuropathologies such as Alzheimer's disease, ischemia, and Huntington's disease among others. Group 1 mGluRs (mGluR1 and mGluR5) are primarily coupled to Gα(q/11) leading to the activation of phospholipase C and the formation of diacylglycerol and inositol 1,4,5-trisphosphate, which results in the release of intracellular calcium stores and protein kinase C (PKC) activation. Desensitization, endocytosis, and recycling are major mechanisms of GPCR regulation, and the intracellular trafficking of GPCRs is linked to the Rab family of small G proteins. Rab8 is a small GTPase that is specifically involved in the regulation of secretory/recycling vesicles, modulation of the actin cytoskeleton, and cell polarity. Rab8 has been shown to regulate the synaptic delivery of AMPA receptors during long-term potentiation and during constitutive receptor recycling. We show here that Rab8 interacts with the C-terminal tail of mGluR1a in an agonist-dependent manner and plays a role in regulating of mGluR1a signaling and intracellular trafficking in human embryonic kidney 293 cells. Specifically, Rab8 expression attenuates mGluR1a-mediated inositol phosphate formation and calcium release from mouse neurons in a PKC-dependent manner, while increasing cell surface mGluR1a expression via decreased receptor endocytosis. These experiments provide us with an understanding of the role Rabs play in coordinated regulation of mGluR1a and how this impacts mGluR1a signaling.

 

Picture: Jessica Esseltine at a Canadian Neuroscience meeting in Vancouver, 2012


In Jessica's words:

"We found that the small G protein Rab8 associates with the G protein-coupled receptor (GPCR) mGluR1a. Through this association, Rab8 inhibits receptor internalization and attenuates signaling in a PKC-dependent manner, resulting in increased overall cell surface mGluR1 expression. Multiple Rabs have been shown to be involved in both endocytic and exocytic events. However, this is the first time a Rab has been shown to inhibit internalization. Therefore, we present a novel role for Rab8 in attenuating mGluR1a internalization and signalling, which opens a new and exciting avenue of research into the role of Rabs in GPCR regulation. Future studies will focus on the role of Rab8 in mGluR signaling during Huntingtin's disease. These proteins have each been implicated in the disease, but the role they play together is not yet defined.

I completed my B.Sc. honors genetics in 2006 from the department of Biology, UWO. I will be leaving in January for a post doc studying A-kinase anchoring proteins in the laboratory of Dr. John D. Scott at the University of Washington, Seattle". 

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