N-methyl-D-aspartate receptor antagonist activity and phencyclidine-like behavioral effects of the pentadecapeptide, [Ser1]histogranin.
The behavioral and pharmacologic profiles of [Ser1]histogranin ([Ser1]HN) were assessed by monitoring its ability to displace the binding of the specific N-methyl-D-aspartate (NMDA) receptor ligand, [3H]CGP 39653, to block the convulsant effects of NMDA and other excitatory agents in mice, and to produce phencyclidine (PCP)-like behavioral effects in rats. The peptide potently inhibited [3H]CGP 39653 binding to membrane preparations of rat brain with an IC50 of 198 nM and a maximal inhibition of 34% of the specific binding activity. Saturation binding experiments with [3H]CGP 39653 in the absence and presence of [Ser1]HN (2 microM) indicated that the inhibitory effect of the peptide was noncompetititive, producing a decrease in the maximal number of binding sites (Bmax of 62.5 fmol/mg protein as compared with 91.3 fmol/mg protein in control), but no significant change in the affinity (Kd of 4.5 nM as compared with 5.1 nM in control). Intracerebroventricular (ICV) injection of [Ser1]HN (10-100 nmol) in mice evoked a dose-dependent and selective blockade of NMDA-induced convulsions. In rats, [Ser1]HN (2.5-100 nmol, ICV) produced dose-dependent stereotypy, ataxia, and locomotion similar to those observed with PCP, at doses ranging between 50 and 400 nmol. The data indicate that [Ser1]HN noncompetitively interacts with the NMDA receptor, an action that goes along with its in vivo NMDA receptor antagonist activity and PCP-like behavioral effects.
Shukla
V K
VK
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Lemaire
S
S
Dumont
M
M
Merali
Z
Z
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010622:Phencyclidine / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
D000927:Anticonvulsants; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; C082312:histogranin; D015763:2-Amino-5-phosphonovalerate; D010622:Phencyclidine