Subsecond regulation of striatal dopamine release by pre-synaptic KATP channels

J Neurochem. 2011 Sep;118(5):721-36. doi: 10.1111/j.1471-4159.2011.07358.x. Epub 2011 Aug 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Analysis of Variance
  • Animals
  • Biophysics / methods
  • Corpus Striatum / cytology*
  • Corpus Striatum / metabolism*
  • Diazoxide / pharmacology
  • Dopamine / metabolism*
  • Dopamine Agonists / pharmacology
  • Electric Stimulation / methods
  • Electrochemistry / methods
  • Glyburide / pharmacology
  • Guinea Pigs
  • Hydrogen Peroxide / pharmacology
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • KATP Channels / metabolism*
  • Mecamylamine / pharmacology
  • Neurons / cytology*
  • Nicotinic Antagonists / pharmacology
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / physiology*
  • Quinpirole / pharmacology
  • Receptors, Drug / metabolism
  • Sulfonylurea Receptors
  • Thiomalates / pharmacology
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism


  • ATP-Binding Cassette Transporters
  • Dopamine Agonists
  • Hypoglycemic Agents
  • KATP Channels
  • Nicotinic Antagonists
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors
  • Thiomalates
  • uK-ATP-1 potassium channel
  • Quinpirole
  • Mecamylamine
  • 2-thiomalic acid
  • Hydrogen Peroxide
  • Tyrosine 3-Monooxygenase
  • Diazoxide
  • Glyburide
  • Dopamine