A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Divergent pharmacological activity of novel marine-derived excitatory amino acids on glutamate receptors
Tekijät: Sanders JM, Ito K, Settimo L, Pentikainen OT, Shoji M, Sasaki M, Johnson MS, Sakai R, Swanson GT
Kustantaja: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
Julkaisuvuosi: 2005
Journal: Journal of Pharmacology and Experimental Therapeutics
Tietokannassa oleva lehden nimi: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Lehden akronyymi: J PHARMACOL EXP THER
Vuosikerta: 314
Numero: 3
Aloitussivu: 1068
Lopetussivu: 1078
Sivujen määrä: 11
ISSN: 0022-3565
DOI: https://doi.org/10.1124/jpet.105.086389
Tiivistelmä
Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogs of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15- to 25-fold lower affinity relative to that of DH for glutamate receptor (GluR)5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for kainate (KA)2 subunits, whereas MSVIII-19 displaced [H-3] kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptor currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogs and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.
Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogs of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15- to 25-fold lower affinity relative to that of DH for glutamate receptor (GluR)5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for kainate (KA)2 subunits, whereas MSVIII-19 displaced [H-3] kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptor currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogs and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.
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