The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of insulin
biosynthesis and secretion, and is one of the key therapeutic targets in the management of
type II diabetes mellitus (DM). Like most GPCRs, the GLP-1R is pleiotropically coupled,
with physiologically relevant signaling pathways including cAMP formation, intracellular
calcium (iCa2+) mobilization and phosphorylation of extracellular signal regulated kinases 1
and 2 (pERK1/2). GLP-1R activity is further complicated by the ability to be activated by
multiple endogenous peptide agonists, and the presence of single nucleotide polymorphisms
(SNPs) within the receptor protein. Additionally, in the absence of complete crystal structures
and limited knowledge of functionally relevant domains other than the N-terminus, this
receptor system is in many respects unexplored. Consequently, the studies comprising this
thesis are focused on illustrating distinct pharmacological concepts at the GLP-1R, while also
addressing the role of a receptor core domain associated with biological activity. Specifically,
the differential actions of allosteric modulators on endogenous peptide ligands (‘probe
dependence’), the differential responses of receptor variants with respect to both orthosteric
and allosteric ligands, and the capacity for both ligand- and pathway-specific effects (‘biased
signaling’) are highlighted. While demonstrating the potential benefits of allosteric
modulation, these studies significantly impact on the approaches and precautions that must be
considered in the design, identification and development of allosteric modulators as
therapeutics. In addition, these studies illustrate the importance of extracellular loop (ECL) 2
in the peptide-mediated activation transition of the GLP-1R. Collectively, this leads to
enhanced understanding of the highly complex GLP-1R system, while also exemplifying the
importance of extended pharmacological analysis of other GPCRs in order to gain a more
comprehensive understanding of receptor systems