An Examination of the Involvement of Phospholipases A₂ and C in the α‐Adrenergic and γ‐Aminobutyric Acid Receptor Modulation of Cyclic AMP Accumulation in Rat Brain Slices

Abstract

Experiments were undertaken to define the role of two calcium‐associated enzyme systems in modulating transmitter‐stimulated production of cylic nucleotides in rat brain. Cyclic AMP (cAMP) accumulation was examined in cerebral cortical slices using a prelabeling technique. The enhancement of isoproterenol‐stimulated cAMP production by α‐adrenergic and γ‐aminobutyric acid‐B (GABAB) agonists was reduced by exposing the tissue to EGTA, a chelator of divalent cations, or quinacrine, a nonselective inhibitor of phospholipase A2. Likewise, chronic (2 weeks) administration of corticosterone decreased the α‐adrenergic and GABAB receptor modulation of second messenger production. Neither cyclooxygenase nor iipoxygenase inhibitors selectively influenced the facilitating response of α‐adrenergic and GABAB agonists. Other experiments revealed that although norepinephrine and 6‐fluoronorepinephrine stimulated inositol phosphate (IP) production in cerebral cortical slices with potencies equal to those displayed in the cyclic nucleotide assay, selective α1,‐adrenergic agonists were less efficacious on IP formation and were without effect in the cAMP assay. Conversely, a selective α2‐adrenergic receptor agonist facilitated the cAMP response to a β‐adrenergic agonist without affecting IP formation. The rank orders of potency of a series of α‐adrenergic antagonists suggest that IP accumulation is mediated solely by α1‐adrenergic receptors, whereas the augmentation of cAMP accumulation is regulated by a mixed population of α‐adrenergic sites. The results suggest that the α‐adrenergic and GABAB receptor‐mediated enhancement of isoproterenol‐stimulated cAMP formation appears to be more closely associated with phospholipase A2 than phospholipase C and may be mediated by arachidonate or some other fatty acid.

Effects of extracellular δ‐aminolaevulinic acid on sodium currents in acutely isolated rat hippocampal CA1 neurons

“…By contrast, baclofen, which is a GABAb receptor agonist, mimicked the effects of ALA on I Na activation and inactivation, suggesting the possible involvement of GABAb receptors in the actions of ALA. GABAb receptors have been shown to be a type of G‐protein‐coupled receptor, the activation of which would lead to multiple intracellular effects, including regulation of phospholipase C (PLC) and A 2 (PLA 2 ), which could be followed by a signaling cascade that liberated arachidonic acid, changed post‐synaptic calcium level, etc. (Duman et al ., 1986; Muzzio et al ., 2001). It was also demonstrated that activation of GABAb receptors could enhance adenylyl cyclase activities by a mechanism involving betagamma subunits of Gi/Go (Olianas & Onali, 1999).…”

Maturation of GABAergic signaling during brainstem development

“…Early studies in brain slices have suggested that facilitation of cyclic AMP formation occurs indirectly, as a consequence of phospholipase A2 stimulation by GABA B receptors and may be mediated by arachidonate or some other fatty acid (Duman, Karbon et al 1986).…”

“…A number of studies have reported many factors which can lead to modulation of GABA B receptors such as cross-talks with other receptors or pathways and interaction with GABA B R associate proteins (Karbon, Duman et al 1984;Karbon and Enna 1985;Duman, Karbon et al 1986;Schaad, Schorderet et al 1989;Olianas and Onali 1999;Simonds 1999;Bowery and Enna 2000;Kubota, Katsurabayashi et al 2003;Balasubramanian, Teissere et al 2004) Cross-talks between PKA and PKC pathways which affect GABA release have also been reported. It has been suggested that the PKC cascade has no direct effects on GABA release, but it is involved in GABA release via cross-talk with the cAMP/PKA (Kubota, Katsurabayashi et al 2003).…”