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Research ArticleArticle

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

Qingbo Tang, Ronnie Gandhoke, Andrew Burritt, Victor J. Hruby, Frank Porreca and Josephine Lai
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 760-765;
Qingbo Tang
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Ronnie Gandhoke
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Andrew Burritt
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Victor J. Hruby
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Frank Porreca
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Josephine Lai
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Abstract

The opioid peptide dynorphin A elicits non-opioid receptor-mediated, neurotoxic response in vivo, which is blocked by pretreatment with MK-801, a noncompetitiveN-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 of125I-(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.

Footnotes

  • Send reprint requests to: Josephine Lai, Ph.D., Department of Pharmacology, The University of Arizona Health Sciences Center, Tucson, AZ 85724. E-mail: lai{at}u.arizona.edu

  • ↵1 This work was supported by National Institutes of Health Grants DA11823 and DA04248.

  • Abbreviations:
    NMDAR
    N-methyl-d-aspartate receptor
    HEK
    human embryonic kidney
    CKA
    7-chlorokynurenic acid
    PMSF
    phenylmethylsulfonyl fluoride
    BSA
    bovine serum albumin
    RP
    reverse phase
    HBS
    HEPES-buffered saline
    • Received April 27, 1999.
    • Accepted July 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

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

Qingbo Tang, Ronnie Gandhoke, Andrew Burritt, Victor J. Hruby, Frank Porreca and Josephine Lai
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 760-765;

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Research ArticleArticle

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

Qingbo Tang, Ronnie Gandhoke, Andrew Burritt, Victor J. Hruby, Frank Porreca and Josephine Lai
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 760-765;
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