title: Activation of cAMP-dependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses.
abstract: In a previous study, we showed that type 1 cannabinoid (CB(1)) receptor activation substantially depresses the corticostriatal glutamatergic transmission onto striatal neurons in the brain slice preparation. We now report that the adenylyl cyclase activator forskolin and cAMP analog (S)-p-8-(4-chlorophenythil) adenosine-3',5'-monophosphorothioate (Sp-8-CPT-cAMPS) strongly suppressed the synaptic depression induced by cannabimimetic aminoalkylindole, WIN 55,212-2. Application of the cAMP-dependent protein kinase (PKA) inhibitor KT5720 alone had no consistent effect on basal synaptic transmission but the synaptic enhancement elicited by forskolin was blocked. In addition, pretreatment of striatal slices with either KT5720 or another PKA inhibitor, H89, completely abolished the attenuation by forskolin on WIN 55,212-2-induced synaptic depression. The effect of forskolin on CB(1) receptor function was still observed in a low Ca(2+) bathing solution, suggesting that the forskolin's action is not attributable to its ability to saturate the presynaptic transmitter release processes. The possibility that forskolin acted by increasing CB(1) receptor phosphorylation was confirmed by demonstrating that the serine-phosphorylated component with CB(1) receptors was significantly increased after forskolin treatment. This forskolin effect was markedly attenuated in the presence of KT5720. Moreover, the activation of beta-adrenergic receptors by isoproterenol mimics forskolin to elicit a PKA-dependent inhibition of CB(1) receptor function. Together, these observations indicate that the presynaptic inhibitory action of CB(1) receptors at corticostriatal synapses could be negatively regulated by cAMP/PKA-mediated receptor phosphorylation. This effect of PKA may play a functional role in fine-tuning glutamatergic transmission at corticostriatal synapses.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Taiwan, Republic of China.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Yea-Lin
authors.initials: YL
authors.lastname: Chen
authors.forename: Shiow-Win
authors.initials: SW
authors.lastname: Lo
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*
chemical_list: D000322:Adrenergic Agonists; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002186:Cannabinoids; D020536:Enzyme Activators; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D009281:Naphthalenes; D011943:Receptors, Adrenergic, beta; D017470:Receptors, Glutamate; D017661:Receptors, Presynaptic; D005576:Colforsin; D012694:Serine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium