title: Subsecond regulation of striatal dopamine release by pre-synaptic KATP channels.
abstract: ATP-sensitive K(+) (K(ATP)) channels are composed of pore-forming subunits, typically Kir6.2 in neurons, and regulatory sulfonylurea receptor subunits. In dorsal striatum, activity-dependent H(2)O(2) produced from glutamate receptor activation inhibits dopamine release via K(ATP) channels. Sources of modulatory H(2)O(2) include striatal medium spiny neurons, but not dopaminergic axons. Using fast-scan cyclic voltammetry in guinea-pig striatal slices and immunohistochemistry, we determined the time window for H(2)O(2)/K(ATP)-channel-mediated inhibition and assessed whether modulatory K(ATP) channels are on dopaminergic axons. Comparison of paired-pulse suppression of dopamine release in the absence and presence of glibenclamide, a K(ATP)-channel blocker, or mercaptosuccinate, a glutathione peroxidase inhibitor that enhances endogenous H(2)O(2) levels, revealed a time window for inhibition of 500-1000 ms after stimulation. Immunohistochemistry demonstrated localization of Kir6.2 K(ATP)-channel subunits on dopaminergic axons. Consistent with the presence of functional K(ATP) channels on dopaminergic axons, K(ATP)-channel openers, diazoxide and cromakalim, suppressed single-pulse evoked dopamine release. Although cholinergic interneurons that tonically regulate dopamine release also express K(ATP) channels, diazoxide did not induce the enhanced frequency responsiveness of dopamine release seen with nicotinic-receptor blockade. Together, these studies reveal subsecond regulation of striatal dopamine release by endogenous H(2)O(2) acting at K(ATP) channels on dopaminergic axons, including a role in paired-pulse suppression.
authors.affiliation: Department of Neurosurgery, New York University School of Medicine, New York, New York 10016, USA. jyotiben.patel@nyumc.org
authors.forename: Jyoti C
authors.initials: JC
authors.lastname: Patel
authors.forename: Paul
authors.initials: P
authors.lastname: Witkovsky
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Rice
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics / Q000379:methods; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004563:Electrochemistry / Q000379:methods; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000378:metabolism*; D008464:Mecamylamine / Q000494:pharmacology; D009474:Neurons / Q000166:cytology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D019257:Quinpirole / Q000494:pharmacology; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D013870:Thiomalates / Q000494:pharmacology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D018491:Dopamine Agonists; D007004:Hypoglycemic Agents; D054086:KATP Channels; D018733:Nicotinic Antagonists; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013870:Thiomalates; C092520:uK-ATP-1 potassium channel; D019257:Quinpirole; D008464:Mecamylamine; C046062:2-thiomalic acid; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; D003981:Diazoxide; D005905:Glyburide; D004298:Dopamine