Regulation of GluA1 AMPA receptor through PKC phosphorylation induced by free fatty acid derivative HUHS2002

Article abstract of DOI:10.1007/s11745-012-3736-4

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 cu

Full text of DOI:10.1007/s11745-012-3736-4

Lipids (2013) 48:23–28
DOI 10.1007/s11745-012-3736-4
ORIGINAL ARTICLE
Regulation of GluA1 AMPA Receptor Through PKC
Phosphorylation Induced by Free Fatty Acid Derivative
HUHS2002
Takaaki Nishimoto
Tadashi Shimizu Akito Tanaka
•
•
Takeshi Kanno
•
•
Tomoyuki Nishizaki
Received: 17 July 2012 / Accepted: 5 October 2012 / Published online: 2 November 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract The present study investigated the effect of
-[4-(Z)-hept-1-enyl-phenoxy] butyric acid (HUHS2002), a
Abbreviations
HUHS2002 4-[4-(Z)-hept-1-enyl-phenoxy] butyric acid
4
newly synthesized free fatty acid derivative, on a-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 lM)-
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
AMPA
a-Amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid
PKC
Protein kinase C
?
2
CaMKII
Ca /calmodulin-dependent protein
kinase II
DCP-LA
8-[2-(2-Pentyl-cyclopropylmethyl)-
cyclopropyl]-octanoic acid
Protein phosphatase 1
PP1
HPLC
High-performance liquid chromatography
2
?
Ca /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.
Introduction
The AMPA receptor plays a pivotal role in excitatory
synaptic transmission. So far, four AMPA receptor sub-
units such as GluA1, GluA2, GluA3, and GluA4 subunits
have been cloned, and the receptors are composed of tet-
ramer containing a solitary subunit or various combinations
of the subunits. Of AMPA receptors GluA1/GluA2 recep-
tor is preferentially expressed in the brain. The GluA1
subunit contains several phosphorylation sites. CaMKII
phosphorylates at Ser831 on the GluA1 subunit, causing an
enhancement in GluA1 AMPA receptor responses [1–6]. In
addition, evidence has pointed to Ser831 phosphorylation
on the subunit by PKC [7]. PKA, alternatively, phosphor-
ylated at Ser845 on the GluA1 subunit, causing an
enhancement in the receptor responses [7, 8].
Keywords HUHS2002 Á GluA1 Á Modulation Á PKC Á
Phosphorylation
T. Nishimoto Á T. Kanno Á T. Nishizaki (&)
Division of Bioinformation, Department of Physiology,
Hyogo College of Medicine, 1-1 Mukogawa-cho,
Nishinomiya 663-8501, Japan
e-mail: tomoyuki@hyo-med.ac.jp
In our earlier study, the cis-unsaturated free fatty acid
2?
arachidonic acid enhanced currents through Ca -permeable
T. Shimizu Á A. Tanaka
Laboratory of Chemical Biology, Advanced Medicinal Research
Center, Hyogo University of Health Sciences, 1-3-6 Minatojima,
Chuo-ku, Kobe 650-8530, Japan
AMPA receptors via a CaMKII pathway [9]. 8-[2-(2-Pentyl-
cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA),
1
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2
4
Lipids (2013) 48:23–28
a linoleic acid derivative, potentiated AMPA receptor
responses by indirectly activating CaMKII due to protein
phosphatase 1 (PP1) inhibition [10]. These findings suggest
that cis-unsaturated free fatty acids or their derivatives are
capable of potentiating AMPA receptor responses in a
CaMKII-dependent manner. An established pathway is that
cis-unsaturated free fatty acids interact with PKC [11]. We
have provided direct evidence for DCP-LA-induced selective
and direct activation of PKC-e [12, 13]. Then, we wondered
whether other free fatty acid derivatives exert their actions
similar to DCP-LA. To address this question, we have syn-
thesized the free fatty acid derivative 4-[4-(Z)-hept-1-enyl-
phenoxy] butyric acid (HUHS2002). We have obtained the
data that HUHS2002 has the potential to inhibit PP1 activity,
thereby indirectly activating CaMKII [14]. HUHS2002
potentiated a7 acetylcholine (ACh) receptor responses in a
CaMKII-dependent manner, regardless of PKC or PKA [14].
The present study was conducted to see the effect of
HUHS2002 on AMPA receptor responses and the under-
lying mechanism. We show here that HUHS2002 potenti-
ates GluA1 receptor responses by activating PKC and in
turn, phosphorylating the receptor at Ser831.
0.914 mmol) slowly at -40 °C under the nitrogen atmo-
sphere. The reaction mixture was stirred for 1 h at -40 °C
and 4-(4-formyl-phenoxy)butyrate (200 mg, 0.846 mmol)
in THF (1 ml) was added at -70 °C. After being stirred for
1 h at -60 °C, the reaction mixture was added with a
saturated aqueous solution of ammonium chloride. The
aqueous layer was extracted with ethyl acetate, and the
combined organic layers were dried over anhydrous
MgSO , and concentrated under reduced pressure. The
4
crude product was purified by silica gel column chroma-
tography (n-hexane/ethyl acetate = 10/1) to give ethyl
4-[(4-(Z)-hept-1-enyl)phenoxy]butyrate (70 mg, 27 %)
1
as a colorless oil. H-NMR (400 MHz, CDCl ) d 0.87
3
(t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.26–1.36
(m, 4H), 1.39–1.45 (m, 2H), 2.10 (tt, J = 7.3 and 7.0 Hz,
2H), 2.29 (ddd, J = 7.4, 7.0 and 7.0 Hz, 2H), 2.53
(t, J = 7.3 Hz, 2H), 4.00 (t, J = 7.0 Hz, 2H), 4.13 (q,
J = 7.1 Hz, 2H), 5.55 (ddd, J = 11.5, 7.4 and 7.4 Hz, 1H),
6.31 (d, J = 11.5 Hz, 1H), 6.83 (d, J = 6.8 Hz, 2H), 7.19
(d, J = 6.8 Hz, 2H).
To a solution of ethyl 4-[(4-(Z)-hept-1-enyl)phen-
oxy]butyrate (66 mg, 0.216 mmol) in dioxane (2 ml) was
added a 1.0 M aqueous solution of lithium hydroxide
(0.430 ml, 0.430 mmol) under ice-cooling. After being
Materials and Methods
stirred for 4 h at room temperature, the reaction mixture
was added to 1 M aqueous solution of HCl. The aqueous
layer was extracted with diethylether, and the combined
Animal Care
organic layers were dried over anhydrous MgSO , and
4
All procedures have been approved by the Animal Care
and Use Committee at Hyogo College of Medicine and
were in compliance with the National Institutes of Health
Guide for the Care and Use of Laboratory Animals.
concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography
(n-hexane/ethyl acetate = 6/1) to give 4-[(4-((Z)-hept-1-
enyl)phenoxy)]butyric acid (HUHS2002) (55 mg, 93 %)
1
as a white solid. H NMR (400 MHz, CDCl ) d 0.89
3
Synthesis of HUHS2002
(t, J = 7.1 Hz, 3H), 1.24–1.38 (m, 4H), 1.38–1.51 (m, 2H),
2.10 (tt, J = 7.3 and 7.0 Hz, 2H), 2.29 (dddd, J = 7.4, 7.0,
To a solution of p-hydroxybenzaldehyde (2.0 g, 16.4 mmol)
and ethyl 4-bromobutyrate (3.6 ml, 19.7 mmol) in DMF
7.0 and 1.4 Hz, 2H), 2.59 (t, J = 7.3 Hz, 2H), 4.03 (t,
J = 7.0 Hz, 2H), 5.56 (ddd, J = 11.5, 7.4 and 7.4 Hz, 1H),
6.32 (dd, J = 11.5 and 1.4 Hz, 1H), 6.85 (d, J = 6.8 Hz,
2H), 7.20 (d, J = 6.8 Hz, 2H): ESI-HRMS (negative ion,
sodium formate) calculated for C H O ([M-H]-)
(12 ml) was added potassium carbonate (2.7 g, 19.7 mmol) at
room temperature. After being stirred for 8 h at 80 °C, the
reaction mixture was added to water. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers
1
7 23 3
275.1653; found 275.1645.
were dried over anhydrous MgSO , and concentrated under
4
reduced pressure. The crude product was purified by silica gel
In-vitro Transcription and Translation
column chromatography (n-hexane/ethyl acetate = 4/1) to
give ethyl 4-(4-formyl-phenoxy) butyrate (3.1 g, 81 %)
mRNAs coding the GluA1 subunit were synthesized
by in-vitro transcription. For the mutant GluA1 subunit,
Ser831 on the GluA1 mRNA was replaced by Ala
[mGluA1(S831A)]. Mature Xenopus oocytes were surgi-
cally removed from female frogs under ether anesthesia
and manually separated from the ovary. Collagenase
(0.5 mg/ml) treatment was carried out to remove the fol-
licular cell layer, and 24 h later oocytes were injected with
approximately 50 nl of mRNAs (1 mg/ml) for the GluA1
1
as a colorless oil. H NMR (400 MHz, CDCl ) d 1.26
3
(
t, J = 7.1 Hz, 3H), 2.15 (tt, J = 7.0 and 7.0 Hz, 2H), 2.53
t, J = 7.0 Hz, 2H), 4.10 (t, J = 7.0 Hz, 2H), 4.16
q, J = 7.1 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 7.83
t, J = 8.7 Hz, 2H), 9.88 (s, 1H).
(
(
(
To a solution of n-hexyltriphenylphosphonium bromide
434 mg, 1.02 mmol) in THF (2.0 ml) was added a 1.0 M
(
THF solution of sodium hexamethyldisilazide (0.914 ml,
1
23

Lipids (2013) 48:23–28
25
subunit or the mGluA1(S831A) subunit, and incubated in
Barth’s solution [in mM: 88 NaCl, 1 KCl, 2.4 NaHCO3,
to terminate the reaction. An aliquot of the solution (20 ll)
was loaded onto a reversed phase high performance liquid
chromatography (HPLC) (LC-10ATvp, Shimadzu Co.,
Kyoto, Japan). A substrate peptide peak and a new product
peak were detected at an absorbance of 214 nm (SPD-
10Avp UV–VIS detector, Shimadzu Co.). It was confirmed
that each peak corresponds to non-phosphorylated and
phosphorylated substrate peptide in the analysis of matrix-
assisted laser desorption ionization time of flight mass
spectrometry (Voyager DE-STR, PE Biosystems Inc.,
Foster city, USA). Areas for non-phosphorylated and
phosphorylated substrate peptide were measured (total area
corresponds to concentration of substrate peptide used
here), and the amount of phosphorylated substrate peptide
was calculated. Phosphorylated substrate peptide (pmol/
min/cell protein weight) was used as an index of PKC
activity.
0
7
.82 MgSO , 0.33 Ca(NO ) , 0.41 CaCl , and 7.5 Tris, pH
4
2 2
2
.6] at 18 °C.
Two-Electrode Voltage-Clamp Recording
Oocytes were transferred to a recording chamber 2–3 days
after injection of each subunit mRNA and continuously
superfused at 22 °C in a standard extracellular solution (in
mM: 88 NaCl, 2 KCl, 1.8 CaCl , and 5 HEPES, pH 7.0) or
2
2
?
Ca -free extracellular solution (in mM: 88 NaCl, 2 KCl, 1
EGTA, and 5 HEPES, pH 7.0). Kainate (100 lM) was
bath-applied to oocytes for 10 s at 10-min intervals before
and after 10 min of treatment with HUHS2002, and kai-
nate-evoked currents were recorded, i.e., the sampling rate
was once per 10 min. It has been established that full
recovery of desensitization for AMPA receptors examined
here is obtained with 10-min washing-out of kainate, based
upon previous experiments. In a two-electrode voltage-
clamp configuration, whole-cell membrane currents were
recorded with a GeneClamp-500 amplifier (Axon Instru-
ments, Inc., Foster city, CA, USA), filtered at 20–50 Hz,
and analyzed on a microcomputer using pClamp software
Statistical Analysis
Statistical analysis was carried out using Dunnett’s test.
Results
(
version 6.0.3, Axon Instruments, Inc.). The electrode used,
with the resistance of 2–3 MX, was filled with 2 M KCl.
HUHS2002 Potentiates Currents Through GluA1
AMPA Receptors
Cell Culture
We initially examined the effect of HUHS2002 on
responses of AMPA receptors consisting the GluA1 sub-
unit alone, expressed in Xenopus oocytes. Kainate
(100 lM), an agonist of AMPA receptors, evoked inward
whole-cell membrane currents (Fig. 1a). The amplitude of
kainate-evoked currents at each period of recording time as
indicated in Fig. 1a was not affected by repetitive appli-
cation with kainate at 10-min intervals in the absence of
HUHS2002 (data not shown), indicating full recovery from
GluA1 AMPA receptor desensitization. HUHS2002
Rat PC-12 cells, that were obtained from RIKEN Cell Bank
(
Tsukuba, Japan), were cultured in Dulbecco’s modified
Eagle’s medium supplemented with 10 % (v/v) heat-inac-
tivated fetal bovine serum, 10 % (v/v) heat-inactivated
horse serum, penicillin (100 U/ml), and streptomycin
(
0.1 mg/ml) in a humidified atmosphere of 5 % CO and
2
9
5 % air at 37 °C.
In-situ PKC Assay
(100 nM) potentiated kainate-evoked whole-cell mem-
PKC activity in PC-12 cells was assayed by the method as
previously described [12]. Cells were treated with
HUHS2002 in the presence and absence of GF109203X at
brane currents to nearly 140 % of original amplitude, the
effect being evident 30 min after 10-min treatment
(Fig. 1a).
3
7 °C for 10 min in an extracellular solution (in mM: 137
The potentiating effect of HUHS2002 was still obtained
2
?
NaCl, 5.4 KCl, 10 MgCl , 5 EGTA, 0.3 Na HPO , 0.4
in Ca -free extracellular solution (Fig. 1c), indicating that
HUHS2002-induced potentiation of GluA1 AMPA recep-
tor currents is due to an enhancement in GluA1 AMPA
2
2
4
K HPO , and 20 HEPES, pH 7.2). Then, cells were rinsed
2
4
2
?
with 100 ll of Ca -free phosphate-buffered saline and
incubated at 30 °C for 15 min in 50 ll of the extracellular
solution containing 50 lg/ml digitonin, 25 mM glycerol
2
?
receptor currents but not in Ca -sensitive chloride channel
currents.
2
-phosphate, 200 lM ATP, and 100 lM synthetic PKC
HUHS2002 potentiated GluA1 AMPA receptor currents
in a bell-shaped concentration (1 nM–1 lM)-dependent
manner, the maximal potentiation being obtained at
100 nM (Fig. 1b).
substrate peptide (Pyr-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-
Tyr-Leu) (Peptide Institute Inc., Osaka, Japan). The
supernatants were collected and boiled at 100 °C for 5 min
1
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Lipids (2013) 48:23–28
Fig. 1 HUHS2002 potentiates GluA1 AMPA receptor currents.c
a GluA1 AMPA receptors were expressed in Xenopus oocytes, and
kainate (KA) (100 lM) was bath-applied to oocytes for 10 s at a
1
(
0-min interval before and after 10-min treatment with HUHS2002
2
HUHS) (100 nM) in Ca -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 lM)-
evoked currents were recorded 10 min before and 30 min after
0-min treatment with HUHS2002 at concentrations as indicated. In
1
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 lM)-evoked currents were
recorded before and after 10-min treatment with HUHS2002
2
?
(
100 nM) in Ca -free extracellular solution. In the graph, each
point represents the mean (± SEM) percentage of original amplitudes
-10 min) (n = 4 independent experiments)
(
HUHS2002 Potentiates GluA1 AMPA Receptor
Currents in a PKC-Dependent Manner
HUHS2002-induced potentiation of GluA1 AMPA recep-
tor currents was significantly inhibited by GF109203X
(
100 nM), an inhibitor of PKC, to an extent similar to that
for the currents elicited from oocytes untreated with
HUHS2002 in the presence of GF109203X, but otherwise
it was not affected by KN-93 (3 lM), an inhibitor of
CaMKII (Fig. 2). This suggests that HUHS2002 potentiates
GluA1 AMPA receptor responses in a PKC-dependent
manner.
To obtain evidence for HUHS2002-induced PKC activa-
tion, we assayed PKC activity in PC-12 cells. HUHS2002
(
1 lM) significantly enhanced PKC activity, and the
enhanced PKC activity was reduced by GF109203X
100 nM), to an extent similar to that for cells untreated with
(
HUHS2002 in the presence of GF109203X (Fig. 3). This
provides evidence that HUHS2002 is capable of activating
PKC.
HUHS2002 Potentiates GluA1 AMPA Receptor
Currents by Phosphorylating the Receptor at Ser831
It is recognized that Ser831 on the GluA1 subunit is
phosphorylated by PKC/CaMKII [1–7]. To see whether
HUHS2002-induced potentiation of GluA1 AMPA recep-
tor currents is due to receptor phosphorylation following
PKC activation, we constructed mutant GluA1 lacking
CaMKII/PKC phosphorylation site [mGluA1(S831A)].
HUHS2002 exhibited no potentiating effect on currents
through mGluA1(S831A) receptors (Fig. 4). This indicates
that HUHS2002 activates PKC, thereby phosphorylating
GluA1 AMPA receptors at Ser831 to potentiate the
receptor currents.
Discussion
The results of the present study clearly demonstrate that the
free fatty acid derivative HUHS2002 potentiates GluA1
AMPA receptor responses. In explanation of this, one
might point to the implication of CaMKII in the HUHS
effect. CaMKII modulates properties of AMPA receptors
1
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Lipids (2013) 48:23–28
27
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 lM)-evoked currents for the receptor were monitored before
Fig. 2 HUHS2002 potentiates GluA1 AMPA receptor currents in a
PKC-dependent manner. Kainate (100 lM)-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)
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)
(
the mean (± SEM) percentage of original amplitudes (-10 min) (n = 4
independent experiments). P values, Dunnett’s test
100 nM) or KN-93 (KN) (3 lM). In the graph, each column represents
CaMKII by inhibiting PP1 [14]. Then, a very complicated
question is why HUHS2002, in spite of CaMKII activation,
potentiates GluA1 AMPA receptor currents in a CaMKII-
independent manner. We have presently no plausible
answer and explanation to this.
Our mounting evidence has shown that a variety of cis-
unsaturated free fatty acids and the linoleic acid derivative
DCP-LA activate PKC [12, 13, 15]. In the present study,
HUHS2002 enhanced PKC activity in PC-12 cells, that is
suppressed by the PKC inhibitor GF109203X, indicating
that like other free fatty acids and DCP-LA HUHS2002
could serve as a PKC activator. cis-Unsaturated free fatty
2
?
acids activate novel PKCs including PKC-e in a Ca - and
diacylglycerol-independent manner or synergistically acti-
vate conventional PKCs, possibly by binding the C1
(
cysteine-rich) domain [11]. In our earlier study, DCP-LA
2
?
directly activated PKC-e under the Ca -free conditions in
the absence of diacylglycerol and phosphatidylserine, and
the DCP-LA-induced PKC-e activation was inhibited by
adding phosphatidylserine [12]. This raises the possibility
that DCP-LA activates PKC-e by binding the phosphati-
dylserine binding site on PKC-e. HUHS2002, in the light of
these facts, might activate PKC by the mechanism sharing
with DCP-LA. To address this point, further experiments
need to be carried out.
Fig. 3 HUHS2002 activates PKC in PC-12 cells. Cells were
untreated and treated with HUHS2002 (1 lM) in the presence and
absence of GF109203X (GF) (100 nM). Phosphorylated substrate
peptide (pmol/min/lg 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
HUHS2002-induced potentiation of GluA1 AMPA
receptor currents was inhibited by GF109203X. This, in the
light of the fact that the GluA1 subunit contains the
CaMKII/PKC phosphorylation site at Ser831 [1–7], implies
that HUHS2002 potentiates GluA1 AMPA receptor
responses in a PKC-dependent manner. In further support
of this note, HUHS2002 had no effect on currents through
mGluA1(S831A) AMPA receptors lacking the CaMKII/
PKC phosphorylation site.
containing the GluA1 subunit through GluA1 phosphory-
lation [1, 2] or CaMKII stimulates delivery of AMPA
receptors towards the membrane surface, causing an
increase in the AMPA receptor conductance [10]. How-
ever, this is unlikely here, since HUHS2002-induced
potentiation of GluA1 AMPA receptor currents was not
affected by KN-93, an inhibitor of CaMKII. We have
obtained the data that HUHS2002 indirectly activates
1
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Lipids (2013) 48:23–28
In conclusion, the results of the present study show that
propionic acid receptor GluR1 subunit by calcium/calmodulin-
dependent kinase II. J Biol Chem 272:32528–32533
. Roche KW, O’Brien RJ, Mammen AL, Bernhardt J, Huganir RL
(1996) Characterization of multiple phosphorylation sites on the
AMPA receptor GluR1 subunit. Neuron 16:1179–1188
8. Keller BU, Hollmann M, Heinemann S, Konnerth A (1992)
Calcium influx through subunits GluR1/GluR3 of kainate/AMPA
receptor channels is regulated by cAMP dependent protein
kinase. EMBO J 11:891–896
the free fatty acid derivative HUHS2002 potentiates GluA1
AMPA receptor responses by activating PKC and phos-
phorylating the receptor at Ser831, independently of
CaMKII activation and phosphorylation. This may provide
further insight into regulation of AMPA receptors by lipids.
7
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
9
. Nishizaki T, Matsuoka T, Nomura T, Enikolopov G, Sumikawa K
(
meable AMPA receptors by interacting with a CaMKII pathway.
Mol Brain Res 67:184–189
2?
1999) Arachidonic acid potentiates currents through Ca -per-
1
0. Kanno T, Yaguchi T, Nagata T, Tanaka A, Nishizaki T (2009)
DCP-LA stimulates AMPA receptor exocytosis through CaMKII
activation due to PP-1 inhibition. J Cell Physiol 221:183–188
1. Nishizuka Y (1995) Protein kinase C and lipid signaling for
sustained cellular responses. FASEB J 9:484–496
2. Kanno T, Yamamoto H, Yaguchi T, Hi R, Mukasa T, Fujikawa
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