beta gamma-mediated enhancement of corticotropin-releasing hormone-stimulated adenylyl cyclase activity by activation of gamma-aminobutyric acid(B) receptors in membranes of rat frontal cortex

Onali, P Olianas, MC

P. Onali et Mc. Olianas, beta gamma-mediated enhancement of corticotropin-releasing hormone-stimulated adenylyl cyclase activity by activation of gamma-aminobutyric acid(B) receptors in membranes of rat frontal cortex, BIOCH PHARM, 62(2), 2001, pp. 183-190

44

INGLESE

Article

Pharmacology & Toxicology

BIOCHEMICAL PHARMACOLOGY

0006-2952 → ACNP

62

2

2001

183 - 190

ISI

0006-2952(20010715)62:2<183:BGEOCH>2.0.ZU;2-B

A number of studies have shown that activation of gamma -aminobutyric acid( B) (GABA(B)) receptors potentiates neurotransmitter-induced accumulation of cyclic AMP in brain slices, but the mechanisms involved in the facilitator y effect have not been fully elucidated. In the present study, we showed th at in membranes of rat frontal cortex the GABA(B) receptor agonist (-)baclo fen increased basal adenylyl cyclase activity and potentiated the maximal e nzyme stimulation elicited by corticotropin-releasing hormone (CRH). The le ss active enantiomer (+)baclofen had no effect on cyclic AMP formation, whe reas the natural agonist GABA mimicked the stimulatory action of (-)baclofe n. In radioligand-binding experiments, the affinity and maximal binding cap acity of I-125-Tyr-CRH was not affected by (-)baclofen. The GABA(B) recepto r antagonist CGP 55845A competitively counteracted the (-)baclofen potentia tion of CRH-stimulated adenylyl cyclase activity with a pA(2) value of 6.70 . Moreover, both (-)baclofen and GABA, but not (+)baclofen, caused a concen tration-dependent stimulation of [S-35]GTP gammaS binding to membrane G-pro teins. The intracerebral injection of pertussis toxin significantly reduced the facilitatory effects of (-)baclofen on both basal and CRH-stimulated a denylyl cyclase activities. Moreover, membrane incubation with the GDP-boun d form of the a subunit of transducin, a scavenger of G protein py subunits , blocked the stimulatory effects of (-)baclofen. The data indicate that in rat frontal cortex activation of GABA(B) receptors potentiates the CRH sti mulation of adenylyl cyclase activity through a mechanism involving the bet a gamma subunits of the pertussis toxin-sensitive G protein G(i)/G(o). (C) 2001 Elsevier Science Inc. All rights reserved.