beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling
| Autor: | Renata Kloc, Ewa M. Urbańska, Marian Wielosz, Sebastian Wnuk, Elzbieta Luchowska, Bartosz Olajossy, Björn Owe-Larsson |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Male medicine.medical_specialty medicine.drug_class Carbazoles 8-Bromo Cyclic Adenosine Monophosphate Biology In Vitro Techniques Kynurenic Acid chemistry.chemical_compound Kynurenic acid Adrenergic Agents Internal medicine Glial Fibrillary Acidic Protein Receptors Adrenergic beta Adrenergic antagonist medicine Animals Pyrroles Protein kinase A signaling Enzyme Inhibitors Rats Wistar Protein kinase A Cyclic GMP Biological Psychiatry Cells Cultured Transaminases Pharmacology Brain Chemistry Dose-Response Relationship Drug L-Lactate Dehydrogenase Antagonist Brain Thionucleotides KT5720 Cyclic AMP-Dependent Protein Kinases Rats Endocrinology chemistry Animals Newborn NMDA receptor Neuroglia Signal Transduction |
| Zdroj: | Progress in neuro-psychopharmacologybiological psychiatry. 33(3) |
| ISSN: | 0278-5846 |
| Popis: | The central levels of endogenous tryptophan metabolite kynurenic acid (KYNA), an antagonist of N-methyl-d-aspartate (NMDA) and alpha7-nicotinic receptors, affect glutamatergic and dopaminergic neurotransmission. Here, we demonstrate that selective agonists of beta(1)-receptors (xamoterol and denopamine), beta(2)-receptors (formoterol and albuterol), alpha- and beta-receptors (epinephrine), 8pCPT-cAMP and 8-Br-cAMP (analogues of cAMP) increase the production of KYNA in rat brain cortical slices and in mixed glial cultures. Neither betaxolol, beta(1)-adrenergic antagonist, nor timolol, a non-selective beta(1,2)-adrenergic antagonist has influenced synthesis of KYNA in both paradigms. In contrast, KT5720, a selective inhibitor of protein kinase A (PKA), strongly reduced KYNA formation in cortical slices (2-10 microM) and in glial cultures (100 nM). beta-adrenergic antagonists and KT5720 prevented the beta-adrenoceptor agonists-induced increases of KYNA synthesis. In vivo, beta-adrenergic agonist clenbuterol (0.1-1.0 mg/kg) increased the cortical endogenous level of KYNA; the effect was blocked with propranolol (10 mg/kg). beta-adrenoceptors agonists, cAMP analogues and KT5720 did not affect directly the activity of KAT I or KAT II measured in partially purified cortical homogenate. In contrast, the exposure of intact cultured glial cells to pCPT-cAMP, 8-Br-cAMP and formoterol has lead to an enhanced action of KATs. These findings demonstrate that beta-adrenoceptor-mediated enhancement of KYNA production is a cAMP- and PKA-dependent event. PKA activity appears to be an essential signal affecting KYNA formation. Described here novel mechanism regulating KYNA availability may be of a potential importance, considering that various stimuli, among them clinically used drugs, activate cAMP/PKA pathway, and thus could counteract the central deficits of KYNA. |
| Databáze: | OpenAIRE |
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