Inhibition of aberrant and constitutive phosphorylation of the high-molecular-mass neurofilament subunit by CEP-1347 (KT7515), an inhibitor of the stress-activated protein kinase signaling pathway
Ek. O'Ferrall et al., Inhibition of aberrant and constitutive phosphorylation of the high-molecular-mass neurofilament subunit by CEP-1347 (KT7515), an inhibitor of the stress-activated protein kinase signaling pathway, J NEUROCHEM, 75(6), 2000, pp. 2358-2367
Previous studies have implicated stress-activated protein kinases (SAPKs) i
n aberrant phosphorylation of the high-molecular-mass neurofilament subunit
(NFH). We now present direct evidence for this involvement using CEP-1347,
a specific inhibitor of SAPK activation. Inhibition by this drug of stress
-induced phosphorylation of NFH and the middle-molecular-mass neurofilament
subunit in the perikaryon of dorsal root ganglion (DRG) neurons paralleled
the decrease in levels of activated SAPKs and was essentially complete at
1 muM CEP-1347. In addition, a role for SAPKs in the constitutive phosphory
lation of NFH was demonstrated. Longterm treatment of unstressed DRG neuron
s with CE-1347 lowered the steady-state phosphorylation level of NFH in neu
rites, No such effect was seen in neurons treated with PD 098059, which blo
cks activation of extracellular signal-regulated kinase 1/2. DRG neurites w
ere shown to contain high basal levels of activated SAPKs. These included a
55-kDa SAPK whose activation was completely abolished at 0.05 muM CEP-1347
and a 45-kDa SAPK that was not affected by the drug. These results indicat
e that SAPKs are involved in both stress-induced and constitutive phosphory
lation of NFH, The differing responses of SAPKs in neurites and cell bodies
to CEP-1347 inhibition further suggest the presence of different signaling
pathways in the two neuronal compartments.