Nav1.7-Ca2+ influx-induced increased phosphorylations of extracellular signal-regulated kinase (ERK) and p38 attenuate tau phosphorylation via glycogen synthase kinase-3beta: priming of Nav1.7 gating by ERK and p38.
In cultured bovine adrenal chromaffin cells expressing Nav1.7 sodium channel isoform, we previously showed that veratridine-induced Na+ influx via Nav1.7 and the subsequent Ca2+ influx via voltage-dependent calcium channels activated protein kinase C-alpha and Akt, which converged on increasing inhibitory Ser9-phosphorylation of glycogen synthase kinase-3beta, decreasing constitutive Ser396-phosphorylation of tau. Here, veratridine increased constitutive Tyr204-phosphorylation of extracellular signal-regulated kinase-1/-2 (ERK1/ERK2) and constitutive Thr180/Tyr182-dual phosphorylation of p38 by approximately 118% (EC50=2.8 microM). Veratridine-induced increased phosphorylation levels of ERK1/ERK2 and p38 were abolished by tetrodotoxin, extracellular Ca2+ removal, or Gö6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole;Go6976] (protein kinase C-alpha inhibitor). PD98059 (2'-amino-3'-methoxyflavone) (ERK1/ERK2 inhibitor) or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] (p38 inhibitor) attenuated veratridine-induced increased phosphorylation of glycogen synthase kinase-3beta and decreased phosphorylation of tau by approximately 54% and approximately 56%, as partial blockade by Gö6976. Additionally, basal constitutive phosphorylation levels of ERK1/ERK2 and p38 were decreased by PD98059 or SB203580, but not by SB216763 [3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indolo-3-yl)-1H-pyrrole-2,5-dione] (glycogen synthase kinase-3beta inhibitor) or extracellular Ca2+ removal. In this condition, PD98059 or SB203580 (but not SB216763 or extracellular Ca2+ removal) inhibited veratridine-induced 22Na+ influx and 45Ca2+ influx, without changing nicotine-induced 22Na+ influx via nicotinic receptor-associated cation channels and nicotine-induced 45Ca2+ influx via voltage-dependent calcium channels. These results suggest that Nav1.7-Ca2+ influx-protein kinase C-alpha pathway activated ERK1/ERK2 and p38, which increased phosphorylation of glycogen synthase kinase-3beta, decreasing tau phosphorylation. In veratridine-nontreated cells, basal constitutive activities of ERK1/ERK2 and p38 primed Nav1.7 to increase 22Na+ influx.
Nemoto
Takayuki
T
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan.
Miyazaki
Satoshi
S
Kanai
Tasuku
T
Maruta
Toyoaki
T
Satoh
Shinya
S
Yoshikawa
Norie
N
Yanagita
Toshihiko
T
Wada
Akihiko
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000737:chemistry / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D002227:Carbazoles; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011978:Receptors, Nicotinic; D015222:Sodium Channels; D016875:tau Proteins; C081021:Go 6976; D013779:Tetrodotoxin; D009538:Nicotine; D014701:Veratridine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium