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Genetic variants among G-protein coupled receptors and implications for cardiovascular disease.

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Call No.	QP552.G16 G64 2009
Author	Gleim, Scott Richard.
Title	Genetic variants among G-protein coupled receptors and implications for cardiovascular disease.
Date	2009
Abstract	Single-nucleotide polymorphisms (SNPs), particularly non-synonymous variants, provide opportunities for deciphering pathophysiological protein influence. An ideal group for realizing these opportunities is the GPCR-superfamily. Principles from rhodopsin are applied to receptors for thromboxane (hTP) and prostacyclin (hIP), which play opposing cardiovascular roles. We report the identification and characterization of naturally-occurring genetic variants in these receptors. Initially, we analyzed zinc interactions with rhodopsin and Retinitis pigmentosa (RP) mutations. These studies identified two conserved zinc-binding motifs mediating receptor destabilization. Site-directed mutagenesis confirmed disruption of native histidine interactions by zinc-binding. Chelation reduced the destabilizing influence of these sites in both wild-type and a common RP mutation. Based on rhodopsin zinc-coordination, we identified similar hTP sites, but not hIP. Saturation binding demonstrates disruption of hTP, but not hIP, with a clear dose-response effect. We sequenced variants from approximately 1000 cardiovascular patients. From 33 variants, we focused on six within the ligand-binding pocket, the ligand-recognition domain, and the G-protein coupling region. Transmembrane variants (V80E and A160T) altered binding, with V80E decreasing affinity, and A160T increasing affinity. Other variants (C68S, E94V, V176E, and V217I) produced non-significant dysfunctions. Altered activation was observed, highlighting agonist and antagonist differences. Finally, mutational "hot spots" observed within these receptors, where mutations preferentially occur, were investigated. We searched for nucleotide patterns in regions flanking the variants. From twelve million human SNPs, significant flanking motifs included CpG-island transition contributions, similar R- and K-type motifs (A/G and G/T, respectively), and an absence of immediately preceding nucleotide influence on S-type variants (C/G). Extending this to other species we find some of these patterns are conserved across species (human, chimpanzee, opossum, mouse, honey bee, bovine, canine, zebrafish, chicken, and rice). This analysis offers the potential to prospectively define sites prone to specific nucleotide alterations. Our studies identified and characterized naturally-occurring genetic variants in counterbalancing prostanoid receptors associated with cardiovascular disease. We developed a semi-automated system for predicting and testing the structural influence of genetic variants in GPCRs. Collectively, our findings provide useful experimental tools to streamline the interpretation of novel GPCR variants which may aid in treatments for cardiovascular disease and a plethora of other human disorders.
Description	xviii, 232 leaves : ill. ; 28 cm
Format	application/pdf
Advisor	John Hwa, Joyce DeLeo Joshua Hamilton, Michael Zegans
Subject	G proteins -- Receptors. Cardiovascular system -- Diseases -- Genetic aspects. Medical Term Receptors, G-Protein-Coupled -- genetics.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
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.285

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	GENETIC VARIANTS AMONG G-PROTEIN COUPLED RECEPTORS AND IMPLICATIONS FOR CARDIOVASCULAR DISEASE A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Scott Richard Gleim DARTMOUTH COLLEGE Hanover, New Hampshire September 30, 2009 ___________________________ (chair) Joyce A. DeLeo, Ph.D. ___________________________ Joshua W. Hamilton, Ph.D. ___________________________ Michael E. Zegans, M.D. ___________________________ (advisor) John Hwa, M.D., Ph.D. ___________________________ Brian W. Pogue, Ph.D. Dean of Graduate Studies

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