METABOTROPIC GLUTAMATE-RECEPTOR AGONISTS POTENTIATE CYCLIC-AMP FORMATION INDUCED BY FORSKOLIN OR BETA-ADRENERGIC-RECEPTOR ACTIVATION IN CEREBRAL CORTICAL ASTROCYTES IN CULTURE
R. Balazs et al., METABOTROPIC GLUTAMATE-RECEPTOR AGONISTS POTENTIATE CYCLIC-AMP FORMATION INDUCED BY FORSKOLIN OR BETA-ADRENERGIC-RECEPTOR ACTIVATION IN CEREBRAL CORTICAL ASTROCYTES IN CULTURE, Journal of neurochemistry, 70(6), 1998, pp. 2446-2458
The metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentan
e-1 S,3R-dicarboxylic acid (ACPD) potentiated the accumulation of cycl
ic AMP induced by either beta-adrenergic receptor stimulation (isoprot
erenol) or direct activation of adenylyl cyclase (AC) with forskolin i
n rat cerebral cortical astrocytes grown in a defined medium. In contr
ast, ACPD inhibits the cyclic AMP response in astrocytes cultured in a
serum-containing medium. Pharmacological characterization indicated t
hat a group I mGluR, of which only mGluR5 is detectable in these cells
, is involved in the potentiation of cyclic AMP accumulation. Potentia
tion was elicited by mGluR I agonists [e.g., (R,S)-3,5-dihydroxyphenyl
glycine (DHPG)], but not by mGluR II or III agonists; it was pertussis
toxin resistant and abolished by procedures suppressing mGluR5 functi
on (phorbol ester pretreatment or DHPG-induced receptor down-regulatio
n). Nevertheless, it appears that products generated through the mGluR
5 transduction pathway, such as elevated [Ca2+](i) or activated protei
n kinase C (PKC), are not involved in the potentiation as it was not i
nfluenced by either the intracellular calcium chelator BAPTA-AM or the
PKC inhibitor Po 31-8220. An inhibitor of phospholipase C, U-73122, m
arkedly attenuated mGluR5-activated phosphoinositide hydrolysis but di
d not significantly affect the DHPG potentiation of the cyclic AMP res
ponse. A mechanism is proposed in which the potentiating effect on AC
could be mediated by free beta gamma complex that is liberated after t
he agonist-bound mGluR5 interacts with its coupled G protein.