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Research ArticleArticle

Activation of G Proteins by Neuropeptide Y and γ-Aminobutyric AcidB Receptor Agonists in Rat Cerebral Cortical Membranes through Distinct Modes of Action

Yuji Odagaki, Nobuyuki Nishi, Shin Nakagawa and Tsukasa Koyama
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1250-1256;
Yuji Odagaki
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Nobuyuki Nishi
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Shin Nakagawa
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Tsukasa Koyama
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Abstract

The neuropeptide Y (NPY)-elicited increase in high-affinity GTPase activity in the rat cerebral cortical membranes was assayed and compared with the γ-aminobutyric acid (GABA)Breceptor-mediated response, representative of the conventional receptor-dependent mode of G protein activation. GABA and a selective GABAB receptor agonist, (±)-baclofen, stimulated the high-affinity GTPase activity in a concentration-dependent and saturable manner, with a strict Mg2+ dependence. On the other hand, NPY (10 μM)-stimulated high-affinity GTPase activity was detectable even in the absence of Mg2+. The concentration-response curve for NPY-induced increase in high-affinity GTPase activity in the presence of 2 mM MgCl2 revealed a biphasic pattern, and NPY (100 nM)-stimulated activity was dependent on MgCl2. In the presence of 2 mM MgCl2, the increase in high-affinity GTPase activity by 100 nM NPY was almost fully inhibited by a selective NPY Y-1 receptor antagonist, (R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide (BIBP3226), whereas the effect of 10 μM NPY was only partially antagonized by this compound. The increase in the activity by 10 μM NPY in the absence of MgCl2 was not at all inhibited by BIBP3226. The high-affinity GTPase activity was augmented by [Leu31,Pro34]NPY (porcine) but not by desamido-NPY, NPY(13-36) (porcine), or rat pancreatic polypeptide at submicromolar concentrations. These results indicate that NPY activates G proteins through two distinct modes of action: the conventional receptor-mediated pathway through NPY Y-1 receptor subtype dominant in the presence of the lower concentrations of NPY and receptor-independent, direct G protein activation driven by the higher concentrations of NPY.

Footnotes

  • Send reprint requests to: Dr. Yuji Odagaki, Department of Psychiatry, Hokkaido University School of Medicine, North 15, West 7, Sapporo 060-8638, Japan.

  • ↵1 This work was supported by a grant-in-aid for Scientific Research (09670970) from the Ministry of Education, Science and Culture of Japan.

  • Abbreviations:
    NPY
    neuropeptide Y
    G protein
    guanine nucleotide-binding regulatory protein
    IAP
    islet-activating protein
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    EC50
    the concentration eliciting the half-maximal effect
    GABA
    γ-aminobutyric acid
    PP
    pancreatic polypeptide
    BIBP3226
    (R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]argininamide
    • Received February 16, 1999.
    • Accepted July 23, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Activation of G Proteins by Neuropeptide Y and γ-Aminobutyric AcidB Receptor Agonists in Rat Cerebral Cortical Membranes through Distinct Modes of Action

Yuji Odagaki, Nobuyuki Nishi, Shin Nakagawa and Tsukasa Koyama
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1250-1256;

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Research ArticleArticle

Activation of G Proteins by Neuropeptide Y and γ-Aminobutyric AcidB Receptor Agonists in Rat Cerebral Cortical Membranes through Distinct Modes of Action

Yuji Odagaki, Nobuyuki Nishi, Shin Nakagawa and Tsukasa Koyama
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1250-1256;
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