Constitutive activity in orphan G protein coupled receptors

<p>"The goal of this research was to use a distal signaling pathway analysis to evaluate the extent of agonist independent constitutive signaling among orphan class-A G protein coupled receptors (GPCRs). These receptors translate extracellular signals via conformational change into intracellular activation of different G proteins and subsequent second messenger synthesis. These small molecules regulate cellular biochemistry, eventually leading to nuclear signaling that results in changes in gene expression. Some GPCRs are capable of signaling in the absence of an activating ligand, a phenomenon called constitutive activity that is inhibited via an "inverse-agonist". The use of cAMP dependent Luciferase expression is used to compare the canonical signaling of all five wild-type Muscarinic Acetylcholine receptors and their constitutively active (CA) mutant counterparts. All five members, both wild-type and CA, signaled via cAMP dependent pathways, although only the CA mutants do so in the absence of an agonist. This technique is then applied to 40 different orphan GPCRs for which an agonist is unknown/not-present. This resulted in 75% (30 out of 40) scoring as constitutively active, grouped into five different categories based on their response. The largest and most significant group of 17 orphans inhibited cAMP dependent expression, both basal and forskolin stimulated, by more than 40%, indicating activation of Gi. In total, novel findings of constitutive activity were found in 23 of the 40 Orphan receptors with results otherwise in agreement with literature in most cases. Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention."--Abstract, page iii.</p>

Name thesis:degree_name

Ph. D. in Chemistry

Grantor

Missouri University of Science and Technology

Year dc:date.available

2016

Author dc:creator

• Martin, Adam Lee

• Receptors
• G-Protein-Coupled
• cAMP
• CRE
• Inverse Agonist
• Biochemistry
• Biology
• Chemistry

Repository record dc:identifier

https://scholarsmine.mst.edu/doctoral_dissertations/2389

OAI identifier oai:identifier

oai:scholarsmine.mst.edu:doctoral_dissertations-3391