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Ionotropic glutamate receptor structure determination by electron microscopy.

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Call No.	QP364.7 .M53 2009
Author	Midgett, Charles.
Title	Ionotropic glutamate receptor structure determination by electron microscopy.
Date	2009
Abstract	α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) function as paracrine and autocrine receptors throughout the body. Most studies have focused on their role in fast excitatory neuronal signaling, and learning and memory. In addition, they are involved in several pathologies, most notably neuro-excitotoxicity. Structural studies of the soluble ligand binding domain coupled with biochemical studies have provided valuable insight into receptor function, especially ligand binding. However, to understand how ligand binding is coupled to channel opening requires structural knowledge of the intact receptor. Previous 3D electron microscopic studies of the receptor, one with recombinantly expressed Ca 2+ -impermeable homomers and the other with brain derived 4M urea washed receptors, produced contradictory models. To resolve this conflict we produced a 3D model of a recombinantly expressed Ca 2+ -permeable homomer using single particle techniques. The models of the recombinantly expressed receptors were similar to each other. Therefore, we concluded the differences between the recombinantly expressed and brain derived receptors was most likely due to the 4M urea wash used in the purification of the brain derived receptors. Furthermore, heteromeric receptors likely share the same structure as the homomeric receptors. To determine the orientation and domain architecture of the receptor we expressed covalently domain labeled receptors. The extra density, due to the labels, was visualized allowing unambiguous assignment of the domains. Placing models of the various domains into the Ca 2+ -permeable model provided insight into how the domains interact. Most notably, the LBD dimers are separated by a central vestibule, and positioned towards the outside of the TMD. This arrangement suggested a model of domain movements during receptor activation. Our model proposes that the TM helices TM1 and TM2 rotate around TM3 to activate the receptor. In addition, this model provides structural insight into biochemical studies of receptor assembly. Further studies of AMPARs must take into account the separation of the LBDs and the idea that the pore is two-fold symmetrical.
Description	xiii, 189 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Madden, Dean, Kull, Jon, Higgs, Henery, Miller, Kieth
Subject	Glutamic acid -- Receptors. Cell receptors -- Structure-activity relationships. Ligand binding (Biochemistry). Glutamates.
College	Dartmouth Medical School -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.318

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Ionotropic Glutamate Receptor Structure Determination by Electron Microscopy A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry by Charles Midgett DARTMOUTH COLLEGE Hanover, New Hampshire MAY 2009 Examining Committee: Dean Madden Ph.D. (chair) Jon Kull Ph.D. Henery Higgs Ph.D. Keith Miller Ph.D. Brian Pogue Ph.D. Dean of Graduate Studies

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