Activation of pre-synaptic M-type K+ channels inhibits [3H]D-aspartate release by reducing Ca2+ entry through P/Q-type voltage-gated Ca2+ channels

J Neurochem. 2009 Apr;109(1):168-81. doi: 10.1111/j.1471-4159.2009.05945.x. Epub 2009 Feb 2.


In this study, the functional consequences of the pharmacological modulation of the M-current (I(KM)) on cytoplasmic Ca(2+) intracellular Ca(2+)concentration ([Ca(2+)](i)) changes and excitatory neurotransmitter release triggered by various stimuli from isolated rat cortical synaptosomes have been investigated. K(v)7.2 immunoreactivity was identified in pre-synaptic elements in cortical slices and isolated glutamatergic cortical synaptosomes. In cerebrocortical synaptosomes exposed to 20 mM [K(+)](e), the I(KM) activator retigabine (RT, 10 microM) inhibited [(3)H]D-aspartate ([(3)H]D-Asp) release and caused membrane hyperpolarization; both these effects were prevented by the I(KM) blocker XE-991 (20 microM). The I(KM) activators RT (0.1-30 microM), flupirtine (10 microM) and BMS-204352 (10 microM) inhibited 20 mM [K(+)](e)-induced synaptosomal [Ca(2+)](i) increases; XE-991 (20 microM) abolished RT-induced inhibition of depolarization-triggered [Ca(2+)](i) transients. The P/Q-type voltage-sensitive Ca(2+)channel (VSCC) blocker omega-agatoxin IVA prevented RT-induced inhibition of depolarization-induced [Ca(2+)](i) increase and [(3)H]D-Asp release, whereas the N-type blocker omega-conotoxin GVIA failed to do so. Finally, 10 microM RT did not modify the increase of [Ca(2+)](i) and the resulting enhancement of [(3)H]D-Asp release induced by [Ca(2+)](i) mobilization from intracellular stores, or by store-operated Ca(2+)channel activation. Collectively, the present data reveal that the pharmacological activation of I(KM) regulates depolarization-induced [(3)H]D-Asp release from cerebrocortical synaptosomes by selectively controlling the changes of [Ca(2+)](i) occurring through P/Q-type VSCCs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium
  • Calcium Channels, P-Type / metabolism*
  • Calcium Channels, Q-Type / metabolism*
  • Cricetinae
  • Cricetulus
  • D-Aspartic Acid / antagonists & inhibitors
  • D-Aspartic Acid / metabolism*
  • Ion Channel Gating / physiology
  • KCNQ2 Potassium Channel / metabolism*
  • Male
  • Presynaptic Terminals / metabolism*
  • Rats
  • Rats, Wistar
  • Tritium / metabolism


  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • KCNQ2 Potassium Channel
  • Tritium
  • D-Aspartic Acid
  • Calcium