Nerve growth factor enhances neurotransmitter release from PC12 cells by increasing Ca(2+)-responsible secretory vesicles through the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase.
Neurotrophins play important roles in the differentiation and survival of neurons during development, and in the regulation of synaptic transmission in adult brain. Brief treatment with nerve growth factor (NGF) enhances depolarization and ionomycin-induced dopamine and acetylcholine release from PC12 cells. The enhancing effect appears very quickly and reaches a plateau 10-15 min after application. NGF also enhances hypertonic solution-induced dopamine release, and increases the amount of dopamine released from membrane-permeabilized PC12 cells in the absence of MgATP, suggesting that NGF enhances neurotransmitter release by increasing the number of Ca(2+)-responsive secretory vesicles. The activation of Trk receptors is essential for NGF action, since K252a abolishes the NGF-induced potentiation of dopamine release and brain-derived neurotrophic factor enhanced ionomycin-induced release only in TrkB-expressing cells. NGF-mediated potentiation of dopamine release is completely abolished by wortmannin, a PI 3-kinase inhibitor, and by U0126 and PD98059, MAP kinase kinase inhibitors, indicating that the activation of PI 3-kinase and MAP kinase pathways is essential for NGF action. These findings suggest that NGF regulates neurotransmitter release through the activation of TrkA receptors, possibly by increasing the number of secretory vesicles in a readily releasable pool.
Amino
Shinya
S
Department of Life Sciences (Biology), Graduate School of Arts and Sciences, The University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan.
Itakura
Makoto
M
Ohnishi
Hiroshi
H
Tsujimura
Jun
J
Koizumi
Shinichi
S
Takei
Nobuyuki
N
Takahashi
Masami
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004789:Enzyme Activation; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D007527:Isoenzymes; D018377:Neurotransmitter Agents; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium