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.
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.
Luisi
Rosa
R
Department of Neuroscience, Division of Pharmacology, University of Naples Federico II, Naples, Italy.
Panza
Elisabetta
E
Barrese
Vincenzo
V
Iannotti
Fabio Arturo
FA
Viggiano
Davide
D
Secondo
Agnese
A
Canzoniero
Lorella Maria Teresa
LM
Martire
Maria
M
Annunziato
Lucio
L
Taglialatela
Maurizio
M
D000818:Animals; D016466:CHO Cells; D002118:Calcium; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D026603:D-Aspartic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology; D051658:KCNQ2 Potassium Channel / Q000378:metabolism*; D008297:Male; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium / Q000378:metabolism
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D051658:KCNQ2 Potassium Channel; D014316:Tritium; D026603:D-Aspartic Acid; D002118:Calcium