title: High-affinity interaction of (des-Tyrosyl)dynorphin A(2-17) with NMDA receptors.
abstract: 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, (125)I-(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 K(d) 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 (125)I-(des-tyrosyl) dynorphin A(2-17), [(3)H]CGP39,653, and [(3)H]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.
authors.affiliation: Department of Pharmacology, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.forename: R
authors.initials: R
authors.lastname: Gandhoke
authors.forename: A
authors.initials: A
authors.lastname: Burritt
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: F
authors.initials: F
authors.lastname: Porreca
authors.forename: J
authors.initials: J
authors.lastname: Lai
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex; D016291:Dizocilpine Maleate / Q000378:metabolism; D004399:Dynorphins / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000502:physiology*; D008297:Male; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017459:Receptors, Amino Acid / Q000145:classification / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D017459:Receptors, Amino Acid; C031959:aspartic acid receptor; C069052:CGP 39653; D016291:Dizocilpine Maleate; D004399:Dynorphins; D015763:2-Amino-5-phosphonovalerate