In the recent past, pharmacological and optical approaches have been employed to gain new insights on the basic mechanisms by which two different ligand systemsâ the.dgcir;parathyroid hormone (PTH) (endocrine and homeostatic) and the PTH-related peptide (PTHrP), autocrine or paracrine mediator of developmental tissuesâ achieve distinct biological effects by acting at the same cell surface receptor, the PTH type 1 receptor (PTHR). This chapter aims to present a comprehensive model to account for the molecular origin of signal differences mediated by the binding of PTH and PTHrP to the PTHR. It covers the kinetic properties of reactions engaged in the PTHR signalling system and endosomal G protein signalling as an emerging hypothesis for PTHR function.