?-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking.

ABSTRACT: A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via ?-arrestin1 and ?-arrestin2. However, the precise roles of the two ?-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two ?-arrestin isoforms and PAC1R, ?-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation. Upon PACAP stimulation, although PAC1R similarly interacted with ?-arrestin1 and ?-arrestin2 in HEK293T cells, the complex of PAC1R and ?-arrestin2 was translocated from the cell surface into cytosol, but that of ?-arrestin1 remained in the cell surface regions in HeLa cells and mouse primary cultured neurons. Silencing of ?-arrestin2 blocked PACAP-induced PAC1R internalization and ERK1/2 phosphorylation, but silencing of ?-arrestin1 increased ERK1/2 phosphorylation. These results show that ?-arrestin1 and ?-arrestin2 exert differential actions on PAC1R internalization and PAC1R-dependent ERK1/2 activation, and suggest that the two ?-arrestin isoforms may be involved in fine and precise tuning of the PAC1R signaling pathways.

SUBMITTER: Shintani Y 

PROVIDER: S-EPMC5937772 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature