TY - JOUR
T1 - Characterization of pardaxin-induced dopamine release from pheochromocytoma cells
T2 - Role of calcium and eicosanoids
AU - Abu-Raya, Saleh
AU - Bloch-Shilderman, Eugenia
AU - Lelkes, Peter I.
AU - Trembovler, Victoria
AU - Shohami, Esther
AU - Gutman, Yehuda
AU - Lazarovici, Philip
PY - 1999/2
Y1 - 1999/2
N2 - Pardaxin, an excitatory neurotoxin, induced dopamine release from pheochromocytoma (PC12) cells both in the presence and absence of extracellular calcium ([Ca](o)). In the presence of extracellular calcium, nifedipine, an L-type calcium channel blocker, did not affect dopamine release, whereas 1,2-bis (2-aminophenoxy) ethane N,N, N'N'-tetra-acetic acid (BAPTA), a chelator of cytosolic calcium, and dantrolene, a blocker of calcium release from intracellular stores, inhibited only partially (30-40%) pardaxin-induced dopamine release. In the absence of [Ca](o), BAPTA and dantrolene were ineffective. Pardaxin stimulated the arachidonic acid (AA) cascade in PC12 cells independently of [Ca](o). The phospholipase inhibitors mepacrine and bromophenacyl bromide inhibited both pardaxin-induced AA release and pardaxin-induced dopamine release. Dopamine release induced by pardaxin also was blocked by the lipoxygenase inhibitors nordihydroguaiaretic acid, esculetin, and 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4- benzoquinone. Under these conditions, a parallel reduction in 5- hydroxyeicosatetranoic acid release also was observed. Suppression of pardaxin-induced dopamine release by inhibitors of phospholipase A2 and lipoxygenase was more pronounced in calcium-free medium. These results indicate the involvement of the lipoxygenase pathway in pardaxin-induced dopamine release and suggest the use of this toxin as a novel pharmacological tool for investigating the mechanism of calcium-independent neurotransmitter release.
AB - Pardaxin, an excitatory neurotoxin, induced dopamine release from pheochromocytoma (PC12) cells both in the presence and absence of extracellular calcium ([Ca](o)). In the presence of extracellular calcium, nifedipine, an L-type calcium channel blocker, did not affect dopamine release, whereas 1,2-bis (2-aminophenoxy) ethane N,N, N'N'-tetra-acetic acid (BAPTA), a chelator of cytosolic calcium, and dantrolene, a blocker of calcium release from intracellular stores, inhibited only partially (30-40%) pardaxin-induced dopamine release. In the absence of [Ca](o), BAPTA and dantrolene were ineffective. Pardaxin stimulated the arachidonic acid (AA) cascade in PC12 cells independently of [Ca](o). The phospholipase inhibitors mepacrine and bromophenacyl bromide inhibited both pardaxin-induced AA release and pardaxin-induced dopamine release. Dopamine release induced by pardaxin also was blocked by the lipoxygenase inhibitors nordihydroguaiaretic acid, esculetin, and 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4- benzoquinone. Under these conditions, a parallel reduction in 5- hydroxyeicosatetranoic acid release also was observed. Suppression of pardaxin-induced dopamine release by inhibitors of phospholipase A2 and lipoxygenase was more pronounced in calcium-free medium. These results indicate the involvement of the lipoxygenase pathway in pardaxin-induced dopamine release and suggest the use of this toxin as a novel pharmacological tool for investigating the mechanism of calcium-independent neurotransmitter release.
UR - http://www.scopus.com/inward/record.url?scp=0033036808&partnerID=8YFLogxK
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C2 - 9918538
AN - SCOPUS:0033036808
SN - 0022-3565
VL - 288
SP - 399
EP - 406
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -