title: Protein kinase C beta regulates the D₂-like dopamine autoreceptor.
abstract: The focus of this study was the regulation of the D2-like dopamine autoreceptor (D2 autoreceptor) by protein kinase Cβ, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing autoreceptors to increase the release of several different neurotransmitters. Here, using both PKCβ(-/-) mice and specific PKCβ inhibitors, we demonstrated that a lack of PKCβ activity enhanced the D2 autoreceptor-stimulated decrease in dopamine release following both chemical and electrical stimulations. Inhibition of PKCβ increased surface localization of D2R in mouse striatal synaptosomes, which could underlie the greater sensitivity to quinpirole following inhibition of PKCβ. PKCβ(-/-) mice displayed greater sensitivity to the quinpirole-induced suppression of locomotor activity, demonstrating that the regulation of the D2 autoreceptor by PKCβ is physiologically significant. Overall, we have found that PKCβ downregulates the D2 autoreceptor, providing an additional layer of regulation for dopaminergic signaling. We propose that in the absence of PKCβ activity, surface D2 autoreceptor localization and thus D2 autoreceptor signaling is increased, leading to less dopamine in the extracellular space and attenuated dopaminergic signaling.
authors.affiliation: Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5632, USA. luderman@umich.edu
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Luderman
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Gnegy
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011485:Protein Binding; D064546:Protein Kinase C beta / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D017448:Receptors, Dopamine D2; D014316:Tritium; D015761:4-Aminopyridine; D064546:Protein Kinase C beta; D004298:Dopamine