Open AccessHDT‐1, a new synthetic compound, inhibits glutamate release in rat cerebral cortex nerve terminals (synaptosomes) 1
Author(s) -
WANG Sujane,
CHOU Shiuhuey,
KUO Yuhchi,
CHOU Shangshing Peter,
TZENG Woanfang,
LEU Jxhyih,
HUANG Rweifen S,
LIEW Yihfong
Publication year - 2008
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2008.00882.x
Subject(s) - glutamate receptor , depolarization , synaptosome , channel blocker , chemistry , biophysics , membrane potential , free nerve ending , 4 aminopyridine , calcium , pharmacology , biochemistry , endocrinology , membrane , biology , potassium channel , receptor , organic chemistry
Aim: Excessive glutamate release has been proposed to be involved in the pathogenesis of several neurological diseases. In this study, we investigated the effect of HDT‐1 (3, 4, 4a, 5, 8, 8a‐hexahydro‐6,7‐dimethyl‐4a‐(phenylsulfonyl)‐2‐tosylisoquinolin‐l(2 H )‐one), a novel synthetic compound, on glutamate release in rat cerebrocortical nerve terminals and explored the possible mechanism. Methods: The release of glutamate was evoked by the K + channel blocker 4‐aminopyridine (4‐AP) or the high external [K + ] and measured by one‐line enzyme‐coupled fruorometric assay. We also determined the loci at which HDT‐1 impinges on cerebrocortical nerve terminals by using membrane potential‐sensitive dye to assay nerve terminal excitability and depolarization, and Ca 2+ indicator Fura‐2 to monitor Ca 2+ influx. Results: HDT‐1 inhibited the release of glutamate evoked by 4‐AP and KC1 in a concentration‐dependent manner. HDT‐1 did not alter the resting synaptosomal membrane potential or 4‐AP‐evoked depolarization. Examination of the effect of HDT‐1 on cytosolic [Ca 2+ ] revealed that the diminution of glutamate release could be attributed to reduction in voltage‐dependent Ca 2+ influx. Consistent with this, the HDT‐1‐mediated inhibition of glutamate release was significantly prevented in synaptosomes pretreated with the N‐ and P/Q‐type Ca 2+ channel blocker ω‐conotoxin MVIIC. Conclusion: In rat cerebrocortical nerve terminals, HDT‐1 inhibits glutamate release through a reduction of voltage‐dependent Ca 2+ channel activity and subsequent decrease of Ca 2+ influx into nerve terminals, rather than any upstream effect on nerve terminal excitability.