DYNORPHIN POTENTIATION OF [H-3] CGP-39653 BINDING TO RAT-BRAIN MEMBRANES

Dynorphin A-(1-13) and related peptide fragments were tested for their ability to modulate the binding of the competitive NMDA receptor antagonist, [H-3]2-amino-4-propyl-5-phosphono-3-pentanoc acid ([H-3]CGP-39653), to rat brain membranes. Dynorphin A-(1-13) produced a dose-dependent (1 nM to 10 mu M) potentiation of [H-3]CGP-39653 binding. The potentiation was insensitive to the kappa-opioid receptor antagonist norbinaltorphimine and it was also observed with the non-opioid peptides dynorphin A-(2-13) and dynorphin A-(6-10). Among various compounds which interact with distinct sites on the NMDA receptor complex, glycine (Gly; 1 mu M) and the Gly receptor antagonist, (+/-)-3-amino-1-hydroxy-2-pyrrolidone ((+/-)-HA-966; 10 mu M), blocked the dynorphin A-(1-13) induced potentiation of [H-3]CGP-39653 binding. In equilibrium binding experiments, dynorphin A-(1-13) (10 mu M) caused a significant increase in the binding capacity (B-max) of [H-3]CGP-39653 (from 111 to 306 fmol/mg protein) but no change in the apparent dissociation constant (K-d Of 8.5 nM as compared with 8.7 nM in the absence of the peptide). The results indicate that dynorphin A and related peptides modify the expression of [H-3]CGP-39653 binding sites consecutive to a non-opioid interaction with the NMDA receptor complex.