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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
Authors:Rosa Luisi,Elisabetta Panza,Vincenzo Barrese,Fabio Arturo Iannotti&dagger  ,Davide Viggiano&dagger  ,Agnese Secondo,Lorella Maria Teresa Canzoniero,Maria Martire&Dagger  ,Lucio Annunziato, Maurizio Taglialatela&dagger  
Affiliation:Division of Pharmacology, Department of Neuroscience, University of Naples Federico II, Naples, Italy;
Department of Health Sciences, University of Molise, Campobasso, Italy;
Institute of Pharmacology, Catholic University of Sacred Heart, Rome, Italy
Abstract:In this study, the functional consequences of the pharmacological modulation of the M‐current (IKM) on cytoplasmic Ca2+ intracellular Ca2+concentration ([Ca2+]i) changes and excitatory neurotransmitter release triggered by various stimuli from isolated rat cortical synaptosomes have been investigated. Kv7.2 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 IKM activator retigabine (RT, 10 μM) inhibited [3H]d ‐aspartate ([3H]d ‐Asp) release and caused membrane hyperpolarization; both these effects were prevented by the IKM blocker XE‐991 (20 μM). The IKM activators RT (0.1–30 μM), flupirtine (10 μM) and BMS‐204352 (10 μM) inhibited 20 mM [K+]e‐induced synaptosomal [Ca2+]i increases; XE‐991 (20 μM) abolished RT‐induced inhibition of depolarization‐triggered [Ca2+]i transients. The P/Q‐type voltage‐sensitive Ca2+channel (VSCC) blocker ω‐agatoxin IVA prevented RT‐induced inhibition of depolarization‐induced [Ca2+]i increase and [3H]d ‐Asp release, whereas the N‐type blocker ω‐conotoxin GVIA failed to do so. Finally, 10 μM RT did not modify the increase of [Ca2+]i and the resulting enhancement of [3H]d ‐Asp release induced by [Ca2+]i mobilization from intracellular stores, or by store‐operated Ca2+channel activation. Collectively, the present data reveal that the pharmacological activation of IKM regulates depolarization‐induced [3H]d ‐Asp release from cerebrocortical synaptosomes by selectively controlling the changes of [Ca2+]i occurring through P/Q‐type VSCCs.
Keywords:excitatory amino acid release    intracellular Ca2+    Kv7.2 subunits    M-current    retigabine    synaptosomes
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