title: Involvement of metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate cyclase activity induced by a novel cognition enhancer NS-105 in rat brain.
abstract: The effect of a novel cognition enhancer [(+)-5-oxo-D-prolinepiperidinamide monohydrate] (NS-105) on cAMP formation was investigated in both slices and membranes of the rat cerebral cortex. NS-105 (10(-8)-10(-6) M) inhibited forskolin-stimulated cAMP formation in membranes, however, the compound significantly enhanced the cAMP formation in pertussis toxin-pre-treated membranes, an action that was abolished by cholera toxin. In contrast, in digitonin-permeabilized membranes, NS-105 had no influence on Mn2+-stimulated cAMP formation. Both of the inhibitory and facilitatory actions of NS-105 on cAMP formation were mimicked by a metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and an adrenergic alpha2 agonist UK-14,304, and blocked by a mGluR antagonist 2-amino-3-phosphonopropanoate but not by an alpha2 antagonist yohimbine. In cortical slices, NS-105 (10(-8)-10(-7) M) inhibited forskolin-stimulated cAMP accumulation but enhanced isoproterenol-stimulated cAMP accumulation, as did by a GABA(B) agonist (-)baclofen. On the other hand, (-)baclofen, while it significantly inhibited cAMP accumulation in slices, did no longer inhibit cAMP accumulation, when treated with NS-105 (10(-8)-10(-5) M). Similarly, (-)baclofen-induced inhibition of the cAMP accumulation was reversed by 1S,3R-ACPD and UK-14,304. NS-105 (10(-6)) increased [35S]GTPgammaS binding in the intact but not digitonin-permeabilized cortical membranes, as produced by UK-14,304, although the compound (10(-9)-10(-3) M) had no influence on various neurotransmitter receptor bindings, including alpha2 receptors. These results suggest that NS-105 modulates adenylate cyclase activity by stimulating mGluRs which might coupled to both Gi/Go and Gs.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Nishiohji Hachijo Minami-ku, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: T
authors.initials: T
authors.lastname: Shimidzu
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikuni
authors.forename: K
authors.initials: K
authors.lastname: Kimura
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D003071:Cognition; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008345:Manganese / Q000494:pharmacology; D037342:Pertussis Toxin; D010880:Piperidines / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C106626:5-oxo-D-prolinepiperidinamide monohydrate; D037361:Adenylate Cyclase Toxin; D000316:Adrenergic alpha-Agonists; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011810:Quinoxalines; D018094:Receptors, Metabotropic Glutamate; D017981:Receptors, Neurotransmitter; D010566:Virulence Factors, Bordetella; C000211:2-amino-3-phosphonopropionic acid; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; D015016:Yohimbine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008345:Manganese; D000068438:Brimonidine Tartrate; D002772:Cholera Toxin; D011392:Proline; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D001418:Baclofen; D007545:Isoproterenol; D000409:Alanine