Muscarinic receptor desensitization and downregulation induced by full and partial cholinergic agonists in rat pancreatic acini

Preincubation of rat pancreatic acini with carbachol, a full cholinergic agonist, for 30 min at 37 degrees C caused a several-fold decrease in the potency of this agonist to elicit amylase release from acini in a subsequent 30-min incubation, but did not reduce its maximal efficacy. Acini preincubated with carbachol were slightly less responsive to cholecystokinin, which utilizes the same intracellular messengers, but were almost completely unresponsive to the partial cholinergic agonist pilocarpine in a second incubation. In contrast, preincubation of acini with pilocarpine for up to 120 min at 37 degrees C failed to alter the subsequent secretory response either to itself or to carbachol. Incubation of pancreatic acini for up to 24 h in a hormonally defined culture medium containing either carbachol or pilocarpine caused a time- and concentration-dependent decrease in cell surface muscarinic cholinergic receptors, as assessed by binding of the labeled muscarinic antagonist [3H]N-methylscopolamine. These results suggest that cholinergic desensitization of secretory responsiveness in the pancreatic acinus is caused by a change in receptor properties distinct from that which elicits removal of the occupied receptor from the cell surface.