beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling.
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.
Luchowska
Elzbieta
E
Department of Experimental and Clinical Pharmacology, Skubiszewski Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.
Kloc
Renata
R
Olajossy
Bartosz
B
Wnuk
Sebastian
S
Wielosz
Marian
M
Owe-Larsson
Bjorn
B
Urbanska
Ewa M
EM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009457:Neuroglia / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D000637:Transaminases / Q000378:metabolism
D018663:Adrenergic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D011758:Pyrroles; D011943:Receptors, Adrenergic, beta; D013873:Thionucleotides; D015124:8-Bromo Cyclic Adenosine Monophosphate; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; C057416:KT 5720; D007770:L-Lactate Dehydrogenase; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D017868:Cyclic AMP-Dependent Protein Kinases; D007736:Kynurenic Acid; D006152:Cyclic GMP