title: Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by α2 adrenoceptor agonist dexmedetomidine.
abstract: The present study examined the effect of dexmedetomidine, an α(2) adrenoceptor agonist, on endogenous glutamate release in rat cerebral cortex nerve terminals (synaptosomes). We also explored the possible mechanism that triggers dexmedetomidine to act. Dexmedetomidine dose-dependently inhibited the release of glutamate evoked by the K(+) channel blocker 4-aminopyridine. Presynaptic α(2A) adrenoceptors were involved in this release inhibition, with the α(2A) antagonist (but not by the α(2B/C) antagonist) blocking the dexmedetomidine-mediated inhibition. The effect of dexmedetomidine on the evoked glutamate release was prevented by the chelating extracellular Ca(2+) ions, and by the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate did not have any effect on the action of dexmedetomidine. Dexmedetomidine decreased the degree of depolarization-induced increase in the intrasynaptosomal Ca(2+) levels, but did not affect the synaptosomal membrane potential. The inhibitory effect of dexmedetomidine on evoked glutamate release was abolished by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but was insensitive to the endoplasmic reticulum ryanodine receptors or mitochondrial Na(+)/Ca(2+) exchange. In addition, the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors prevented dexmedetomidine from inhibiting glutamate release. Further, western blotting showed that dexmedetomidine decreased the 4-aminopyridine-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 and synapsin I, the main presynaptic target of mitogen-activated protein kinase. Thus, we concluded that dexmedetomidine acts at α(2A) adrenoceptors present on cerebrocortical nerve terminals inhibit the release of glutamate. We further concluded that this effect is linked to the suppression of voltage-dependent Ca(2+) channels and mitogen-activated protein kinase activity.
authors.affiliation: Center of Cardiovascular, Far Eastern Memorial Hospital, Banqiao Dist., New Taipei City, 220, Taiwan.
authors.forename: Kuan-Ming
authors.initials: KM
authors.lastname: Chiu
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lu
authors.forename: Su-Jane
authors.initials: SJ
authors.lastname: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology*; D020927:Dexmedetomidine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D015761:4-Aminopyridine; D058647:Adrenergic alpha-2 Receptor Agonists; D002118:Calcium; D020864:Calcium Channels, N-Type; D020927:Dexmedetomidine; D018698:Glutamic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018341:Receptors, Adrenergic, alpha-2; C503279:Cacna1b protein, rat