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Research Focus and Highlights
Dr. Martin Beinborn’s research interests focus on the molecular processes that lead to ligand-induced activation of peptide hormone receptors, and the downstream triggering of intracellular signaling cascades. As a model system to explore the underlying mechanisms, he has been working over the past several years on the G-protein coupled receptors (GPCRs) for the gastrointestinal hormone/neurotransmitter cholecystokinin (CCK). Mutational analysis of recombinant CCK receptors led to the identification of two distinct yet interacting processes that determine agonist-induced receptor activation: (i) ligand-specific interactions at selected amino acids within a putative receptor transmembrane domain binding pocket, and (ii) the equilibrium set point between ‘active’ and ‘inactive’ receptor conformations. It is of note that there is evidence for multiple ‘active’ receptor conformations that may be differentially activated by a given CCK receptor ligand and that can induce in the selective stimulation of different intracellular second messenger systems (e.g., inositol phosphate formation vs. cAMP production).
More recently, Dr.Beinborn’s group has begun to explore to what extent these general principles as developed for CCK receptors (categorized as class A, rhodopsin-type GPCRs) are applicable to members of the class B subfamily of receptors (which share a seven transmembrane domain topology yet have no sequence homology with the class A proteins). The latter studies focus on the receptors for glucagon-like peptides (GLP), which are important physiological regulators of blood glucose levels, satiety, and resorption of nutrients through the intestinal mucosa. Specific projects that are currently pursued in the Beinborn lab include (i) to identify amino acids, both in the GLP-1 receptor and in its peptide ligands, that are triggers of second messenger signaling; (ii) to investigate compatibility of GLP-1 receptor stimulation with the ‘extended ternary model’, a molecular theory of receptor activation that has been formulated based on class A receptor function, and (iii) to explore the mechanisms underlying tonic activity of the GLP-1 receptor when this protein is expressed in the context of highly differentiated pancreatic beta cells. These studies, centered around different aspects of GLP-1 receptor function, may accelerate the discovery of novel non-peptide agonists that can mimic the function of endogenous hormone. Such compounds, given their potential to facilitate glucose-induced insulin secretion, hold considerable promise as a future pharmacotherapy of type II diabetes.
Research Administrator: Dionne Marshall
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