This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

Title

Amino Acids 855 to 876 of the Rodent Metabotropic Glutamate Receptor, mGluR5, C Terminal Domain Are Responsible for Its Inner Nuclear Membrane Localization

Date of Award

Spring 5-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

ABSTRACT OF THE DISSERTATION

Traditionally G-protein coupled receptors (GPCR) are thought to be located on

the cell surface and to transmit extracellular signals into the cytoplasm. A growing

number of GPCRs, however, have been localized to several subcellular compartments

including the inner nuclear membrane (INM). One such receptor is the metabotropic

glutamate receptor 5 (mGluR5) which is not only expressed on the plasma membrane

(PM) but is also expressed on the INM mediating Ca2+ changes in the nucleoplasm by

coupling with Gq/11. In the present study, we identified a region in the proximal part of

the mGluR5 C terminus (amino acids 855-876) which is required for INM localization of

the receptor. Specifically, replacement of intracellular C terminus of another PM GPCR,

GABAB2, with the mGluR5 C terminus led to the nuclear membrane (NM) localization of

the chimeric receptor. Further, immunocytochemistry, fractionation and Ca2+ imaging

techniques revealed that mGluR5 amino acids 855-876 are required for INM localization.

Although these amino acids contain a small basic amino acid stretch akin to bona fide

nuclear localization sequences, their mutation did not prevent INM localization. These

data suggest that mGluR5 either uses a non-canonical mechanism to localize to the INM

and/or that it diffuses there and is subsequently anchored via other interactions. A

retention model is supported by immunoprecipitation and chromatin immunoprecipitation

experiments showing that mGluR5 interacts with nuclear resident biomolecules like

Lamin B1 and chromatin. Taken together, this study defines a region in mGluR5 C

terminus required for its INM localization and suggests that nuclear retention is an

important mechanism in this localization process.

Language

English (en)

Chair and Committee

Karen L O'Malley

Committee Members

Thomas J Baranski, Narasimhan Gautam, Robert W Gereau, Phyllis I Hanson, Didier Hodzic

Comments

Permanent URL: https://doi.org/10.7936/K7M906K1

This document is currently not available here.

Share

COinS