Studies in the Friedman laboratory focus on regulation of parathyroid hormone receptor signaling and regulated trafficking. PTH controls extracellular calcium and phosphate homeostasis. PTH effects on kidney and bone are mediated by its cognate receptor, the type I PTH receptor (PTH1R). Key advances have been made in understanding cell-specific PTH1R signaling and trafficking. Recent observations indicate that PTH1R activation, desensitization and endocytosis are mediated through distinct structural states that derive from specific interactions between ligand and receptor. Agonist- or antagonist-occupied receptor states induce discrete conformations with accessibility to intracellular receptor domains. The differential or inducible involvement of these domains in coupling to G proteins may represent a molecular basis for ligand-selective responses not only for the PTH1R, but also for other G protein-coupled receptors. Current work is directed at elucidating the molecular and structural mechanisms of how cytoplasmic scaffold proteins such as NHERF1 and Dishevelled legislate cell-, ligand-, and stage-specific receptor trafficking.
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