Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery

Cassandra Renee Koole, Emilia Elizabeth Savage, Arthur Christopoulos, Laurence J Miller, Patrick Sexton, Denise Laura Wootten

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of beta-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1 or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.
Original languageEnglish
Pages (from-to)1234 - 1244
Number of pages11
JournalMolecular Endocrinology
Volume27
Issue number8
DOIs
Publication statusPublished - 2013

Cite this

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title = "Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery",
abstract = "The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of beta-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1 or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.",
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Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery. / Koole, Cassandra Renee; Savage, Emilia Elizabeth; Christopoulos, Arthur; Miller, Laurence J; Sexton, Patrick; Wootten, Denise Laura.

In: Molecular Endocrinology, Vol. 27, No. 8, 2013, p. 1234 - 1244.

Research output: Contribution to journalArticleResearchpeer-review

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