Activation of cAMP-dependent protein kinase suppresses the presynaptic cannabinoid inhibition of glutamatergic transmission at corticostriatal synapses

Chiung Chun Huang, Yea Lin Chen, Shiow Win Lo, Kuei Sen Hsu

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31 Citations (Scopus)

Abstract

In a previous study, we showed that type 1 cannabinoid (CB1) 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 CB1 receptor function was still observed in a low Ca2+ 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 CB1 receptor phosphorylation was confirmed by demonstrating that the serine-phosphorylated component with CB1 receptors was significantly increased after forskolin treatment. This forskolin effect was markedly attenuated in the presence of KT5720. Moreover, the activation of β-adrenergic receptors by isoproterenol mimics forskolin to elicit a PKA-dependent inhibition of CB1 receptor function. Together, these observations indicate that the presynaptic inhibitory action of CB1 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.

Original languageEnglish
Pages (from-to)578-585
Number of pages8
JournalMolecular Pharmacology
Volume61
Issue number3
DOIs
Publication statusPublished - 2002 Mar 6

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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