It has been widely assumed that the production of the ubiquitous second messenger cyclic AMP, which is mediated by cell surface G protein–coupled receptors (GPCRs), and its termination take place exclusively at the plasma membrane. Recent studies reveal that diverse GPCRs do not always follow this conventional paradigm. In the new model, GPCRs mediate G-protein signaling not only from the plasma membrane but also from endosomal membranes. This model proposes that following ligand binding and activation, cell surface GPCRs internalize and redistribute into early endosomes, where trimeric G protein signaling can be maintained for an extended period of time. This Perspective discusses the molecular and cellular mechanistic subtleties as well as the physiological consequences of this unexpected process, which is considerably changing how we think about GPCR signaling and regulation and how we study drugs that target this receptor family.
This perspective article in the latest Nature chemical biology journal, summarizes some of the recent work on the complicated world of endosomal signaling of GPCRs. Although it looks obvious in hindsight, it is quite mind boggling to realize that the different receptor conformations (stabilized by different ligands) dictates the activations of g-protein signaling pathways not just on the cell surface but also inside the cells!
Figure: (a) Studies in cells led to the discovery that PTH, as opposed to PTHrP, sustains G-protein activity and cAMP production after PTHR internalization into early endosomes. (b) This observation is changing how we think about cellular signaling of the PTHR and is motivating the development of PTH analogs able to promote the endosomal cAMP signaling. One of them, LA-PTH, mediates a markedly prolonged cAMP signaling response in cells and prolonged hypercalcemic responses when injected into mice. (c) LA-PTH is now in preclinical development via the US National Institutes of Health BrIDGs program63 for eventual testing as a future treatment for hypoparathyroidism.
It will not surprise me if further evidence comes to light, in the near future, that other signaling pathways (beta-arrestin, PKA, PKC, etc) are also directly or indirectly activated from endosomal membranes.
