Studies in my laboratory focus on spatiotemporal regulation of protein-protein interactions governing GPCR signaling and function. We are especially interested in the parathyroid hormone receptor (PTHR), which controls extracellular mineral ion homeostasis and bone turnover. Key advances have been made in understanding cell-specific PTHR signaling, trafficking, and post-translational modifications. Recent observations indicate that PTHR activation, desensitization and endocytosis are mediated through distinct structural states that derive from specific interactions between ligand andreceptor. 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 notonly for the PTHR, but also for other G protein-coupled receptors, and are novel drug targets. Current work is directed at elucidating the molecular and structural mechanisms of how cytoplasmic PDZ proteins such as NHERF1 legislate cell-, ligand-, and stage-specific receptor trafficking. The resulting information will be valuable in understanding mineral ion homeostasis under normal conditions, as well as disordered calcium balance in renal failure, hyperpara­thyroidism, or osteoporosis. 

---

Important Publications

Alonso V and PA Friedman.  Ubiquitination-regulated G protein-coupled receptor signaling and trafficking.  Mol Endocrinol 27:558-572, 2013.

Wang B, Y Yang, L Liu, HC Blair and PA Friedman.  NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts.  Bone 52:268-277, 2013.

Wang B, CK Means, Y Yang, T Mamonova, A Bisello, DL Altschuler, JD Scott and PA Friedman.  Ezrin-anchored PKA coordinates phosphorylation-dependent disassembly of a NHERF1 ternary complex to regulate hormone-sensitive phosphate transport.  J Biol Chem doi:10.1074/jbc M112.369405, 2012.

Liu L, V Alonso, L Guo, I Tourkova, SE Henderson, AJ Almarza, PA Friedman and HC Blair.  Na+/H+-exchanger regulatory factor-1 (NHERF1) directly regulates osteogenesis.  J Biol Chem 287:43312-43321, 2012.

Mamonova T, M Kurnikova and PA Friedman.  Structural basis for NHERF1 PDZ domain binding affinity.  Biochemistry 51:3110-3120, 2012.