Metabotropic glutamate receptor agonists potentiate cyclic AMP formation induced by forskolin or beta-adrenergic receptor activation in cerebral cortical astrocytes in culture.
The metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) potentiated the accumulation of cyclic AMP induced by either beta-adrenergic receptor stimulation (isoproterenol) or direct activation of adenylyl cyclase (AC) with forskolin in rat cerebral cortical astrocytes grown in a defined medium. In contrast, ACPD inhibits the cyclic AMP response in astrocytes cultured in a serum-containing medium. Pharmacological characterization indicated that a group I mGluR, of which only mGluR5 is detectable in these cells, is involved in the potentiation of cyclic AMP accumulation. Potentiation was elicited by mGluR I agonists [e.g., (R,S)-3,5-dihydroxyphenylglycine (DHPG)], but not by mGluR II or III agonists; it was pertussis toxin resistant and abolished by procedures suppressing mGluR5 function (phorbol ester pretreatment or DHPG-induced receptor down-regulation). Nevertheless, it appears that products generated through the mGluR5 transduction pathway, such as elevated [Ca2+]i or activated protein kinase C (PKC), are not involved in the potentiation as it was not influenced by either the intracellular calcium chelator BAPTA-AM or the PKC inhibitor Ro 31-8220. An inhibitor of phospholipase C, U-73122, markedly attenuated mGluR5-activated phosphoinositide hydrolysis but did not significantly affect the DHPG potentiation of the cyclic AMP response. A mechanism is proposed in which the potentiating effect on AC could be mediated by free betagamma complex that is liberated after the agonist-bound mGluR5 interacts with its coupled G protein.
Balázs
R
R
Institute for Brain Aging and Dementia, University of California, Irvine 92697-4540, USA.
Miller
S
S
Chun
Y
Y
O'Toole
J
J
Cotman
C W
CW
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004963:Estrenes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012118:Resorcinols / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D015854:Up-Regulation
D000318:Adrenergic beta-Agonists; D004963:Estrenes; D018690:Excitatory Amino Acid Agonists; C578937:Grm5 protein, rat; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D064529:Receptor, Metabotropic Glutamate 5; D011943:Receptors, Adrenergic, beta; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D005576:Colforsin; C079215:3,5-dihydroxyphenylglycine; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D005998:Glycine