Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Parathyroid hormone receptor signaling and trafficking: new insights and perspectives (#198)

Nathan Pavlos 1
  1. The University of Western Australia, Nedlands, WA, Australia

Parathyroid hormone (PTH) and its cognate type-I receptor (PTHR) are critical for hormone regulation of skeletal growth and mineral-ion homeostasis. Activation and signaling of the PTHR has long served as a useful paradigm for other G-protein coupled receptors (GPCRs). Like other GPCRs, PTHR actions commence upon ligand binding at the cell surface. Recent findings unveil several novel and unexpected insights into PTHR signaling and trafficking that are changing our perception of GPCR signaling and function. First, accumulating evidence suggests that signaling by PTHR is not limited to the cell surface but exhibits persistent G protein signaling upon on ligand-induced internalisation into endosomes. This endosomal PTHR signaling is referred to as ‘non-canonical’ to distinguish it from the transient signaling restricted to the plasma membrane. Termination of non-canonical PTHR signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Second, parallel studies are now revealing new clues as to the nature and structural determinants of these PTHR trafficking chaperones. This presentation summarises recent advances in our understanding in PTHR signaling and trafficking with particular emphasis on the SNX27-retromer cargo sorting complex, a major endosomal sorting hub that is responsible for the recycling and preservation of a multitude of vital cell surface signaling receptors including those which augment PTHR function. These findings are integrated into a unified model of PTHR trafficking and functional implications for signal transduction and bone and mineral-ion metabolism discussed.