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Lipids
2013 Jan 01;481:23-8. doi: 10.1007/s11745-012-3736-4.
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Regulation of GluA1 AMPA receptor through PKC phosphorylation induced by free fatty acid derivative HUHS2002.
Nishimoto T
,
Kanno T
,
Shimizu T
,
Tanaka A
,
Nishizaki T
.
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The present study investigated the effect of 4-[4-(Z)-hept-1-enyl-phenoxy] butyric acid (HUHS2002), a newly synthesized free fatty acid derivative, on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses. HUHS2002 potentiated currents through GluA1 AMPA receptors expressed in Xenopus oocytes in a bell-shaped concentration (1 nM-1 μM)-dependent manner, the maximum reaching nearly 140 % of original amplitude at 100 nM. The potentiation was significantly inhibited by GF109203X, an inhibitor of protein kinase C (PKC), but not KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). HUHS2002 had no potentiating effect on currents through mutant GluA1 AMPA receptors with replacement of Ser831, a PKC/CaMKII phosphorylation site, by Ala. In the in situ PKC assay using rat PC-12 cells, HUHS2002 significantly enhanced PKC activity, that is suppressed by GF109203X. Overall, the results of the present study show that HUHS2002 potentiates GluA1 AMPA receptor responses by activating PKC and phosphorylating the receptors at Ser831, regardless of CaMKII activation and phosphorylation.
Fig. 1. HUHS2002 potentiates GluA1 AMPA receptor currents. a GluA1 AMPA receptors were expressed in Xenopus oocytes, and kainate (KA) (100 μM) was bath-applied to oocytes for 10 s at a 10-min interval before and after 10-min treatment with HUHS2002 (HUHS) (100 nM) in Ca2+-containing extracellular solution. The holding potential was −60 mV. Application with KA is indicated by bars. Typical currents recorded 10 min before and 30 min after treatment with HUHS2002 are shown. In the graph, each point represents the mean (±SEM) percentage of original amplitudes (−10 min) (n = 5 independent experiments). b Kainate (100 μM)-evoked currents were recorded 10 min before and 30 min after 10-min treatment with HUHS2002 at concentrations as indicated. In the graph, each column represents the mean (±SEM) percentage of original amplitudes (−10 min) (n = 5–7 independent experiments). P value as compared with current amplitudes before treatment with HUHS2002, Dunnett’s test. c Kainate (100 μM)-evoked currents were recorded before and after 10-min treatment with HUHS2002 (100 nM) in Ca2+-free extracellular solution. In the graph, each point represents the mean (±SEM) percentage of original amplitudes (−10 min) (n = 4 independent experiments)
Fig. 2. HUHS2002 potentiates GluA1 AMPA receptor currents in a PKC-dependent manner. Kainate (100 μM)-evoked currents were monitored 10 min before and 30 min after 10-min treatment with HUHS2002 (100 nM) in the absence and presence of GF109203X (GF) (100 nM) or KN-93 (KN) (3 μM). In the graph, each column represents the mean (±SEM) percentage of original amplitudes (−10 min) (n = 4 independent experiments). P values, Dunnett’s test
Fig. 3. HUHS2002 activates PKC in PC-12 cells. Cells were untreated and treated with HUHS2002 (1 μM) in the presence and absence of GF109203X (GF) (100 nM). Phosphorylated substrate peptide (pmol/min/μg cell protein) was used as an index of PKC activity. In the graph, each column represents the mean (±SEM) PKC activity (n = 8 independent experiments). P value, Dunnett’s test
Fig. 4. HUHS2002 potentiates GluA1 AMPA receptor currents through PKC phosphorylation of the receptor. mGluA1 (S831A) AMPA receptors were expressed in Xenopus oocytes. Kainate (100 μM)-evoked currents for the receptor were monitored before and after 10-min treatment with HUHS2002 (100 nM). In the graph, each point represents the mean (±SEM) percentage of original amplitudes (−10 min) (n = 4 independent experiments)
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