Glycogen synthase kinase 3 activation is essential for the snake phospholipase A2 neurotoxin-induced secretion in chromaffin cells.
Neuroendocrine chromaffin cells were used to study the mechanism of the snake phospholipase A2 (PLA2) neurotoxin enhancement of exocytosis. Notexin, beta-bungarotoxin, taipoxin or textilotoxin enhanced the fast release of catecholamines elicited by flash photolysis of cytosolic caged calcium. Such an increase correlates with the capacity of these neurotoxins to cause fragmentation of the F-actin cortical barrier with subsequent accumulation of vesicles in the proximity of the plasma membrane. These PLA2 neurotoxins do not act via protein kinase C activation, which is known to promote F-actin fragmentation. Lithium, RO31-8220 and SB216763, three inhibitors of the glycogen synthase kinase 3, prevent both the alteration of the F-actin peripheral cortex and the enhancement of fast release elicited by these neurotoxins. In addition, glycogen synthase kinase 3 has been detected by immunolocalization in a membranous compartment of the chromaffin cell endoplasmic reticulum (ER). These results suggest that the activation of this enzyme plays a major role in the enhancement of exocytosis of the readily releasable granules caused by PLA2 neurotoxins in neuroendocrine chromaffin cells.
Giner
Daniel
D
Instituto de Neurociencias, Centro Mixto CSIC-Universidad Miguel Hernández, Campus de San Juan, 03550 Alicante, Spain.
López
Inmaculada
I
Neco
Patricia
P
Rossetto
Ornella
O
Montecucco
Cesare
C
Gutiérrez
Luis M
LM
D000199:Actins / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000378:metabolism*; D004546:Elapid Venoms / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009466:Neuromuscular Blocking Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D017729:Presynaptic Terminals / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012910:Snake Venoms / Q000378:metabolism*; D012911:Snakes
D000199:Actins; D004546:Elapid Venoms; D004791:Enzyme Inhibitors; D009466:Neuromuscular Blocking Agents; D009498:Neurotoxins; D012910:Snake Venoms; C005082:notexin; C015523:taipoxin; C037525:textilotoxin; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D010741:Phospholipases A; D054467:Phospholipases A2