4-Bromohomoibotenic acid selectively activates a 1-aminocyclopentane-1S,3R-dicarboxylic acid-insensitive metabotropic glutamate receptor coupled to phosphoinositide hydrolysis in rat cortical slices.
Glutamate activates a family of receptors, known as metabotropic glutamate receptors (mGluRs), that are coupled to various second messenger systems through G proteins. All mGluR subtypes characterized to date in rat brain slices are activated by the glutamate analogue 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD). However, few agonists are available that selectively activate specific mGluR subtypes. We report that the glutamate analogue (R,S)-4-bromohomoibotenate (BrHI) stimulates phosphoinositide hydrolysis in rat cerebral cortical slices in a concentration-dependent manner (EC50 = 190 microM). The response to BrHI is stereoselective and is not blocked by ionotropic glutamate receptor antagonists. It is interesting that the responses to BrHI and 1S,3R-ACPD are completely additive, suggesting that these responses are mediated by different receptor subtypes. Consistent with this, the response to BrHI is insensitive to L-2-amino-3-phosphonopropionic acid (L-AP3), whereas the response to 1S,3R-ACPD is partially blocked by L-AP3. BrHI does not activate metabotropic receptors coupled to changes in cyclic AMP accumulation or activation of phospholipase D. Thus, BrHI seems to activate specifically a phosphoinositide hydrolysis-linked mGluR that is insensitive to 1S,3R-ACPD. This compound may prove useful as a tool for elucidating the roles of different mGluR subtypes in mammalian brain.
Chung
D S
DS
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.
Winder
D G
DG
Conn
P J
PJ
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance; D004789:Enzyme Activation; D006868:Hydrolysis; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000032:analysis / Q000502:physiology*
C023365:4-methylhomoibotenic acid; D000067956:Adenylyl Cyclase Inhibitors; D010716:Phosphatidylinositols; D017470:Receptors, Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C023366:4-bromohomoibotenic acid; D007051:Ibotenic Acid; D000242:Cyclic AMP; D010739:Phospholipase D