Agonist-specific desensitization of PGI2-stimulated cyclic AMP accumulation by PGE1 in human foreskin fibroblasts.

Agonist-specific desensitization of prostaglandin I2-stimulated (PGI2)1 adenosine 3':5'-monophosphate (cyclic AMP) accumulation can be demonstrated in intact human foreskin fibroblasts (HFF) following a single exposure to PGE1 or a stable PGI2 analog (nitrilo-PGI2). A single PGI2-stimulation of HFF cells does not result in desensitization. Continuous re-addition of PGI2 over a 4 hr period does induce desensitization to subsequent PGI2-stimulation. HFF cells that are desensitized to PGI2 are also desensitized to PGE1 or nitrilo-PGI2 stimulation indicating that these agonists share a common adenylate cyclase complex. Desensitization to PGI2 can be measured after a 60 min, but not after a 30 min, exposure to PGE1 or nitrilo-PGI2. Once HFF cells are desensitized, a 12-24 hr period is required for the recovery of PGI2 sensitivity. The adenylate cyclase in membranes prepared from intact cells that were preincubated with PGE1 is also desensitized to subsequent PGI2-stimulation. Preincubation of cells with PGI2 does not induce desensitization of PGI2-stimulated adenylate cyclase. These data suggest that HFF cells must be constantly exposed to a biologically active prostaglandin for desensitization to occur. The intrinsic chemical lability of PGI2 may be a biochemical protection mechanism against desensitization in cells that normally respond to PGI2.