Modulation of agonist stimulated adenylyl cyclase and GTPase activity by l-pro-l-leu-glycinamide and its peptidomimetic analogue in rat striatal membranes

Abstract l -Prolyl- l -leucyl-glycinamide (PLG), also known as melanocyte-stimulating hormone release inhibiting factor (MIF-1), is an endogenous brain tripeptide. Previous studies have shown that PLG, and its peptidomimetic analogues, render dopamine D 2 receptors more responsive to agonists by maintaining the high-affinity binding state of the receptors. In the present study, we examined the effect PLG and its analogue 3( R )-[(2( S )-pyrrolidylcarbonyl)amino]-2-oxo-l-pyrrolidineacetamide (PAOPA) on dopamine-stimulated adenylyl cyclase and NPA-stimulated GTPase activity in rat striatal membranes. Dopamine-stimulated adenylyl cyclase activity was inhibited by both PLG and PAOPA in a dose-dependent manner, whereas R (−)-propylnorapomorphine (NPA)-stimulated low K m GTPase activity was significantly increased by 1 μM PLG or 1 nM PAOPA. These results suggest that PLG and PAOPA maintain the high affinity state of the D 2 receptor by increasing GTP hydrolysis through stimulation of agonist-induced GTPase activity.