Arrestin mediated GPCR biased signaling and its application in new drug discovery / 中国药理学与毒理学杂志

ABSTRACT

G protein coupled receptors (GPCR) are important transmembrane proteins which account for more than 30% of direct clinical drug targets. Two main signaling pathways, either mediated by different G protein subtype or arrestins, underlies most of 800 GPCR functions in human genome. Selective ligands targeting to one of the G protein or arrestin signaling through specific receptor, which is also called biased ligands, may have beneficial effects and delete the unwanted side effects compared with traditional full agonists or antagonists. However, the mechanism governing the arrestin mediated GPCR biased signaling is still unclear. In recent years, our research group have combined animal models, cell biology and biophysical approaches to address the arrestin mediated GPCR function and its underlying mechanism, which is a key issue for GPCR targeted drug discovery. We have identified that downstream of β2 adrenergic receptor, arrestin mediated signaling plays critical roles in maintaining the pancreatic islet homeostasis and promotes the learning and memory through regulation of astrocyte-neuron lactate transportation cycle. Targeting β- arrestin- 1 signaling rather than Gq signaling down?stream of CCK1R receptor may provide a better therapy for diabetes. Although arrestin mediated signaling was traditionally recognized as the second wave of GPCR signaling, our recent results indicated that β-arrestin-1 was able to induce the first wave signaling in to regulate the catecholamine secretion from adrenal gland, by directly mediating AT1R/TRPC3 coupling. This result provided new mode for the connection of GPCR to activation of ion channels. Moreover, all above arrestin mediated signaling are regulated by receptor phosphorylation barcode, a hypothesis brought up by Prof. Lefkowitz and Prof. Andrew Tobin. Using biophysical and cellular approaches, we have identified that the 10 distinct phosphorylation interacting sites along the N-terminal of arrestin is the ″phospho-code″ reader of the arrestin, which recognized the information passed by GPCR, then translated to more than 1000 distinct arrestin conformations, and recruit distinct downstream signaling molecule. We therefore proposed″a flute model″ working mechanism for arrestin mediated GPCR signaling. Using this flute model combined with GPCR ligand identification, we were able to regulate specific signaling and therefore arrestin mediated physiological functions by activation of the receptor and operation of the receptor phosphorylation barcode simultaneously (unpublished results). These knowledge advances in arrestin mediated GPCR signaling may facilitate further drug development targeting to GPCR family members.