Dynorphin block of N-methyl-D-aspartate channels increases with the peptide length.

We examined the non-opioid actions of various forms of dynorphin A (DynA) on N-methyl-D-aspartate (NMDA) receptor channels in isolated rat trigeminal neurons using the whole-cell patch recording technique. All the dynorphins tested blocked NMDA-activated currents. The blocking actions were voltage-independent. The IC50 was 0.26 microM for DynA(1-32), 6.6 microM for DynA(1-17) 7.4 microM for DynA(1-13), 42.0 microM for DynA(1-10). DynA(1-8) had no detectable blocking action on NMDA responses. Thus, the IC50s of dynorphins for NMDA receptors increased 160-fold as the length of the peptides decreased from 32 to 10 amino acids. Amidation of dynorphins dramatically reduced their IC50s and eliminated the large difference in the IC50s of various lengths of dynorphins. The reduction in the IC50s of dynorphin amides could not be explained by the resistance of the peptides to enzymatic degradation. Our observations suggest that peptide processing affects dynorphin blocking actions on NMDA responses. The positively charged residues, lengths of the peptides and amidation may contribute to their affinities for NMDA receptors.