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Vol. 291, Issue 2, 760-765, November 1999

High-Affinity Interaction of (des-Tyrosyl)Dynorphin A(2-17) with NMDA Receptors1

Qingbo Tang, Ronnie Gandhoke, Andrew Burritt, Victor J. Hruby, Frank Porreca and Josephine Lai

Departments of Pharmacology (Q.T., R.G., F.P., J.L.) and Chemistry (A.B., V.J.H.), The University of Arizona, Tucson, Arizona

The opioid peptide dynorphin A elicits non-opioid receptor-mediated, neurotoxic response in vivo, which is blocked by pretreatment with MK-801, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. In the present study, we examined the possible direct interaction of dynorphin A on the NMDAR. A nonopioid dynorphin A analog, 125I-(des-tyrosyl) dynorphin A(2-17), was used in radioligand binding analysis on rat cortical brain membranes. This radioligand exhibited a saturable, specific binding at high affinity with a Kd value of 9.4 ± 1.6 nM and maximal binding of 2.4 ± 0.6 pmol/mg protein. This binding site was associated with the NMDAR complex because it was modulated by a number of NMDAR ligands. Transient expression of the rat NR1a/NR2A complex in human embryonic kidney 293 cells confirmed a coexpression of 125I-(des-tyrosyl) dynorphin A(2-17), [3H]CGP39,653, and [3H]MK-801 binding. These data provide direct evidence of the presence of a high-affinity binding site for dynorphin A on the NMDAR. The modulatory effect of the various NMDAR-selective ligands on dynorphin A binding suggests that dynorphin A may bind preferentially to the closed/desensitized state of the NMDAR. The physiological role of dynorphin A binding to the NMDAR remains to be established.

0022-3565/99/2912-0760$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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