1 Program in Neuroscience, 3 Program in Cellular and Molecular Physiology, 2 Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We recently reported that
arachidonic acid (AA) inhibits L- and N-type Ca2+ currents
at positive test potentials in the presence of the dihydropyridine L-type Ca2+ channel agonist (+)-202-791 in dissociated
neonatal rat superior cervical ganglion neurons [Liu L and Rittenhouse
AR. J Physiol (Lond) 525: 291-404, 2000]. In this
first of two companion papers, we characterized the mechanism of
inhibition by AA at the whole cell level. In the presence of either
-conotoxin GVIA or nimodipine, AA decreased current amplitude,
confirming that L- and N-type currents, respectively, were inhibited.
AA-induced inhibition was concentration dependent and reversible with
an albumin-containing wash solution, but appears independent of AA
metabolism and G protein activity. In characterizing inhibition, an
AA-induced enhancement of current amplitude was revealed that occurred
primarily at negative test potentials. Cell dialysis with albumin
minimized inhibition but had little effect on enhancement, suggesting
that AA has distinct sites of action. We examined AA's actions on
current kinetics and found that AA increased holding
potential-dependent inactivation. AA also enhanced the rate of N-type
current activation. These findings indicate that AA causes multiple
changes in sympathetic Ca2+ currents.
calcium channel; 5,8,1,14-eicosatetraynoic acid; FPL-64176; fatty acid; oleic acid
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
ARACHIDONIC ACID (AA; C20:4, n-6), a cis-polyunsaturated fatty acid, appears to serve as an intracellular messenger in a variety of receptor-mediated signal transduction cascades (3, 43). After the stimulation of G protein-coupled receptors, activated phospholipases liberate AA from phospholipids in the plasma membrane (35). A major effect of increased free AA is the modulation of ion channel activity including voltage- and ligand-gated channels and intracellular Ca2+ release channels (24, 30, 46, 48). The coordinated modulation of these channels by AA can result in changes in membrane excitability (12). AA appears to exert its actions by either direct binding to channel proteins or indirectly via molecules downstream of AA, including AA metabolites, free radicals, AA-sensitive phosphatases, and/or protein kinases (24, 30, 46, 48).
We are interested in understanding how AA modulates voltage-gated Ca2+ currents in neurons, since Ca2+ entry plays important roles in coordinating electrical activity with many cellular processes, such as neurotransmitter release, enzyme activation, and gene expression (9). Few studies have examined the effects of AA on Ca2+ currents in neurons; however, in each case, AA inhibited high threshold-activated whole cell Ca2+ currents (16, 25, 26, 44). We previously examined the effects of AA on Ca2+ currents in neonatal rat superior cervical ganglion (SCG) neurons (29). In these neurons, the majority of the whole cell Ba2+ current is N-type current. The remaining current is mostly L-type current; a small residual current appears to be non-L- or N-type (36, 39). At the whole cell level, we found that AA decreases both L- and N-type Ca2+ currents (29). From cell-attached patch recordings, we found that AA has no effect on unitary current amplitude, but inhibits the activity of both L- and N-type channels. Decreased activity is due in part to an increase in the incidence of null sweeps, suggesting that AA promotes inactivation (29). While inhibition of Ca2+ currents appears to predominate in neurons, enhancement as well as inhibition of Ca2+ currents by AA has been reported in non-neuronal cells (11, 19, 41, 52). These observed differences in action raise the possibility that AA modulates Ca2+ currents by more than one mechanism; however, whether both of these processes are active in neurons is unknown.
In this study, we investigated the mechanism by which AA inhibits whole
cell Ca2+ currents in neonatal rat SCG neurons using
Ba2+ as the charge carrier. We report here that AA-induced
inhibition is reversible and concentration dependent. Furthermore, in
the presence of the N-type Ca2+ channel blocker
-conotoxin GVIA (
-CgTx) or in the presence of the L-type
Ca2+ channel antagonist nimodipine (NMN), AA decreased the
whole cell current, confirming that AA inhibits both L- and N-type
currents. In characterizing the inhibitory actions of AA, we found
that, while AA inhibited currents at positive test potentials, AA
enhanced currents at negative potentials. Cell dialysis with bovine
serum albumin (BSA) minimized the inhibitory actions of AA, while
enhancement remained, indicating that AA may have more than one site of
action in SCG neurons. We also examined whether AA modulated whole cell current kinetics. We found that AA increased holding
potential-dependent inactivation and selectively increased the
activation kinetics of N-type current. The accompanying paper describes
an association of enhancement with the increase in activation of N-type
current by AA acting either at the extracellular surface or within the outer leaflet of the cell membrane (6).
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
SCG neuron preparation. SCG were removed from 1- to 4-day old Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) following decapitation. Neurons were mechanically dissociated by trituration (18) and plated on poly-L-lysine (Sigma, St. Louis, MO)-coated glass coverslips and incubated at 37°C in a 5% CO2 environment. Cells were maintained in DMEM supplemented with 7.5% calf serum, 7.5% fetal bovine serum, 4 mM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin (all from Sigma), and 0.2 µg/ml nerve growth factor (Bioproducts for Science, Indianapolis, IN). Cells were used within 12 h to avoid recording from neurons with processes.
Whole cell current recording conditions.
Whole cell Ba2+ currents were measured by the method of
Hamill et al. (15) with an Axopatch 200A or 200B (Axon
Instruments, Foster City, CA) or Dagan 3900 (Dagan, Minneapolis, MN)
patch-clamp amplifier at room temperature (20-24°C). Pipette
capacitance was zeroed on sealing. Whole cell capacitive transients
were compensated by ~70% in most experiments. Currents were low-pass
filtered at 2 or 5 kHz using the four-pole Bessel filter in the clamp
amplifier and sampled at 20 kHz except where noted. Current traces were stored and later analyzed on a personal computer using CED Patch 6.3 acquisition and analysis programs (Cambridge Electronic Design, Cambridge, UK) or a PDP-11 computer using custom-written software. Electrodes were made from borosilicate glass capillaries (Drummond Scientific, Broomall, PA) and heat-polished to a tip diameter of ~1
µm. When filled with internal solution, the pipette resistance ranged
from 2.0 to 3.0 M. During the recording, changes in the bath
solution were made by gravity-driven perfusion.
Solutions and drugs.
The external solution was composed of (in mM) of 20 barium acetate, 125 N-methyl-D-glucamine (NMG)-aspartate, 10 HEPES,
and 0.0005 tetrodotoxin (TTX; 293 mosmol/l; Research Biochemicals, Natick, MA or Sigma). The pipette solution was composed of (in mM) 123 cesium aspartate, 10 HEPES, 0.1 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 5 MgCl2, and 4 ATP (264 mosmol/l; Sigma). For experiments measuring the effects of AA in the presence of EGTA (Aldrich, Milwaukee, WI), the pipette solution was composed of (in mM) 123 cesium
aspartate, 10 EGTA, 10 HEPES, 5 MgCl2, and 4 ATP (296 mosmol/l); the NMG aspartate in the external solution was raised to 135 mM unless indicated otherwise. In some experiments, 0.4 mM
GTP (Sigma) or 0.1 mM guanosine 5'-O-(2-thiodiphosphate)
(GDPS; Research Biochemicals or Sigma) was also included in the
pipette solution. The pH of all solutions was adjusted to 7.5 with CsOH.
Data analysis.
Before analysis, leak and residual capacitive transients were minimized
by subtracting from each trace a scaled up current elicited with a
hyperpolarizing test pulse. In some figures, residual transients that
remained after leak subtraction were digitally removed. Whole cell
current amplitudes, defined as the peak current, were measured 15 ms
after the start of the test pulse. For experiments where long-lasting
tail currents were elicited in the presence of the L-type
Ca2+ channel agonist FPL-64176, tail currents were measured
~13 ms after the membrane was stepped from +10 mV to a tail potential of 40 mV. Data analysis began 1-2 min following breakthrough to
ensure complete dialysis of the cell with the nucleotides contained in
the pipette solution, a time delay shown to be sufficient to maximally
affect G protein activity in these cells (5).
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
AA inhibits whole cell L- and
N-type currents in SCG neurons.
To characterize the inhibitory effects of AA on whole cell L- and
N-type currents in SCG neurons, a voltage protocol originally developed
by Plummer et al. (36, 37) was used to isolate L-type from
N-type currents. Membrane voltage was held at 90 mV, stepped to +10
mV for 20 ms, and then stepped back to an intermediate potential of
40 mV. Under control conditions, only 4.3 ± 0.7 pA of current
was present 13 ms following the step from +10 mV to the tail potential
(n = 12). When the nondihydropyridine L-type Ca2+ channel agonist FPL-64176 (1 µM) was present in the
bath, a long-lasting component of the tail current made up
entirely of L-type current was elicited (Fig.
1A) and
averaged 225.7 ± 42.9 pA (n = 12). This component
of current was monitored as a measure of L-type current. The peak
current was monitored as a measure of N-type current since
the majority of it is inhibited by
-CgTx (36). Furthermore, in contrast to the tail current, FPL-64176 increased the
peak current only modestly (Fig. 1A): on average 25.8 ± 5.9% (n = 12).
|
|
|
|
Current inhibition appears independent of AA
metabolism.
AA can be metabolized by several pathways to generate biologically
active products, some of which have been shown to modulate ion channel
activity (24, 30, 35). To examine the possible involvement
of a metabolite in current inhibition, selective inhibitors were used
to block the three common pathways of AA metabolism (24).
The cyclooxygenase pathway was inhibited by indomethacin (4), the lipoxygenase pathway was inhibited by ETI
(4), and the cytochrome P-450 oxygenase or
"epoxygenase" pathway was inhibited by the suicide substrate
1-aminobanzotriazole (1-ABT) (16, 17). Each inhibitor was
used at a concentration shown previously to block a particular
metabolic pathway (see Fig. 5). FPL-64176
was included in the bath solution so that both the peak and
long-lasting tail currents could be monitored simultaneously. We first
examined whether bath application of any of the inhibitors for at least
2 min altered whole cell currents, and found no effect on either the
peak or the long-lasting tail current (data not shown).
|
AA increases holding potential-dependent
inactivation of whole cell currents.
In our cell-attached patch experiments, AA increased the incidence of
null sweeps for both L- and N-type Ca2+ channel activity
but had no effect on fast inactivation in sweeps with activity
(29). These findings suggest that AA enhances a slow form
of inactivation, one that develops over many seconds, such as holding
potential-dependent inactivation. To investigate whether AA has any
effects on holding potential-dependent inactivation that can be
observed at the whole cell level, inactivation curves were generated in
the absence and presence of 5 µM AA using the protocol shown in Fig.
6A. We
found that AA significantly increased the level of inactivation
compared with controls at positive holding potentials (Fig.
6B).
|
The actions of AA on whole cell currents are voltage
dependent.
To determine whether the effects of AA on whole cell currents are
sensitive to test potential, current amplitude (Fig.
7A) was
measured at test potentials from 60 to +80 mV in 10-mV increments in
the absence and presence of 5 µM AA. No Ca2+ channel
ligand (i.e., blocker or agonist) was present in the bath during these
experiments. The current-voltage (I-V) plots (Fig.
7B) show that the threshold of current activation was
similar in the absence and presence of AA (approximately
30 mV). In
addition, the reversal potentials were similar (around +60 mV).
However, we did find that the effects of AA on current amplitude varied with the test potential. AA significantly decreased the currents elicited from +10 to +50 mV (P < 0.05). Surprisingly, the
I-V curves also revealed that AA significantly enhanced
current amplitude at negative potentials (
20 and
10 mV, P
< 0.05), raising the possibility that AA has another effect on
whole cell currents in addition to inhibition.
|
Internal BSA blocks AA-induced
inhibition but not enhancement.
The I-V relationships and activation curves indicate that AA
inhibits currents at positive test potentials and may enhance currents
at negative test potentials (Fig. 7, B and D). To
verify that enhancement of current by AA is stable and reproducible, and not an artifact of the experimental protocol, the time courses of
the development of current enhancement and inhibition were examined
concurrently. Currents were measured by applying alternating test
pulses to +10 or 10 mV from a holding potential of
90 mV, as shown
in Fig. 8A. When 5 µM AA was
applied, currents elicited at +10 mV were initially enhanced. At this
voltage, enhancement was then offset by a decrease in current
amplitude, leading to significant inhibition (40.5 ± 9.7%)
measured after 7 min (Fig. 8B, left bars). In contrast, at
10 mV enhancement dominated after 5 min of AA, such that the current
was increased by 155 ± 28.1% (Fig. 8C, left bars).
|
AA increases the activation kinetics of
N-type currents.
Last, we examined whether AA changes the activation kinetics of
currents elicited at a test potential of +10 mV. To more clearly visualize any changes in activation kinetics, sweeps collected 5 min
after the application of 5 µM AA were normalized so that the plateau
phase of the current was superimposed onto that of the control sweep.
Using this procedure, we found that AA (5 µM) accelerated the rate of
activation in five of five cells (Fig. 9A). A similar increase in the
rate of activation was also observed in three of three cells when
FPL-64176 was present in the bath solution (Fig.
10A). In contrast, 5 µM
myristic acid (data not shown; n = 3) and 5 µM oleic
acid (Fig. 9B; n = 3) had no obvious effect on the activation kinetics when FPL-64176 was included in the
bath solution, indicating that, like inhibition, the kinetic change
shows some specificity for AA.
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Modulation of Ca2+ currents by AA has been described in a number of different cell types (24, 30). However, studies examining the effects of AA on Ca2+ currents in neurons are few. Here, we used pharmacological and biophysical methods to isolate whole cell L- and N-type Ca2+ currents in SCG neurons to characterize the effects of AA on them. We confirmed that AA inhibits both L- and N-type currents at positive test potentials and revealed an enhancement of whole cell currents at negative test potentials. In addition, AA produced two kinetic changes: an increase in holding-potential-dependent inactivation and a selective increase in activation kinetics of N-type current.
In characterizing the inhibition by AA of whole cell L- and N-type
Ca2+ currents in SCG neurons, we have found that it is
sensitive to micromolar concentrations of AA, a concentration range
that is considered physiological (see Ref. 29 for further
discussion). The effects of AA are partially reversible and at least
somewhat specific for AA since three structurally similar fatty acids
failed to inhibit the current. In addition, inhibition appears
unaffected by the level of G protein activity. Whole cell current
inhibition by AA has been observed in other neuronal preparations,
although the channel types affected were not identified (17, 25,
26, 44). Whether these reported actions of AA are physiological was questioned, since the 25 or 50 µM concentrations of AA used in
these studies were considered high. At these concentrations, AA may be
above its critical micellar concentration, which has been estimated to
be ~10 µM in a balanced salt solution containing 1 mM
Ca2+ (40). If so, the actual AA concentration
in solution in these studies may have been lower. Another concern with
the use of higher AA concentrations is that the presence of micelles
might interfere with channel gating, obscuring the physiological
actions of AA. It is unknown whether micelles do form at high
concentrations of AA under our recording conditions. Empirically, we
(data not shown) and others (33, 54) have found that bath
application of AA does destabilize whole cell current recordings at
concentrations 50 µM. However, the inhibition of L- and
N-type currents in SCG neurons by AA occurs at lower
concentrations (5 µM) where we have not had this problem.
In addition to inhibiting L- and N-type currents, AA-induced enhancement of whole cell currents could be observed at negative voltages in the I-V relationships (Fig. 7B) and in plots of current amplitude vs. time (Fig. 8A). When cells were dialyzed with BSA, enhancement remained while inhibition was minimized, suggesting that the site of inhibition may be at the internal leaflet of the membrane or may occur at an intracellular location. Moreover, these results suggest that AA may enhance whole cell currents by acting either on external portions of a transmembrane protein, such as the Ca2+ channel itself, or in the outer leaflet of the membrane. It is also possible that enhancement occurs by AA acting with much higher affinity at an intracellular site such that BSA's affinity for AA is insufficient to block enhancement. Either mechanism argues for distinct sites of action for enhancement and inhibition. In our companion paper, we have characterized whole cell current enhancement by AA. We have confirmed that AA's site of action appears to be on the extracellular surface or outer leaflet of the cell membrane since bath application of an AA analog that cannot cross the membrane mimicked enhancement but not inhibition (6). We also have found that application of AA causes no observable enhancement of unitary L- or N-type Ca2+ channel activity when recorded at +30 mV in the cell-attached patch configuration (29), consistent with whole cell data where inhibition dominates at positive test potentials.
AA increased the amount of inactivation that occurs at positive holding potentials. In other cell types, AA decreased whole cell L-type Ca2+ currents (32, 45, 51), at least in part by shifting the inactivation curve more negative (33, 44, 45, 55). These results suggest that, although AA increases inactivation in a number of cell types, the exact mechanism of action may vary. At the cell-attached level, AA inhibits both L- and N-type Ca2+ channel activity similarly by increasing the incidence of null sweeps (29), consistent with the AA-induced increase in holding potential inactivation observed at the whole cell level (Fig. 6). Thus increases in channel inactivation are most likely associated with inhibition. In addition to the increase in null sweeps, we found that, in sweeps with activity, mean closed time increased (29). This change may also contribute to AA-induced decreases in whole cell current amplitude.
In addition to changes in inactivation, AA increases the activation kinetics of whole cell N-type currents. These data are in contrast to our single channel results where AA increased the first latency (29). This discrepancy may be due to the observation that, when L- and N-type channels did open in the presence of AA, they did so on average with a first latency >50 ms followed by quite low activity (29). Therefore, at the whole cell level, we would predict that AA-inhibited channels contribute little to the whole cell current because so few of these channels will have opened by the end of the 20-ms test pulse. Furthermore, the increase in whole cell activation kinetics by AA may be independent of AA's inhibitory effects since current inhibition is largely eliminated when BSA is dialyzed into the cell (Fig. 8), whereas faster activation kinetics remain unchanged (6). Indeed, regression analysis performed in our companion paper (6) indicates that the increased rate of current activation is directly correlated with the magnitude of current enhancement. Thus it appears that, with inhibition, AA increases first latency (29), whereas with enhancement activation kinetics increase. Thus, in contrast to inhibition, we would expect the increased rate of activation, which is associated with enhancement, to be observed at the single channel level as a decrease in first latency.
Our findings may resolve some of the controversy in the field
concerning the differing effects of AA on Ca2+ currents.
Previous reports of AA-induced current enhancement vs. inhibition
(24) appear to show conflicting results; this may be due
to one or more of the actions reported here, rather than to nonspecific
effects. Whether AA exerts its actions on Ca2+ currents in
SCG neurons directly or indirectly remains unanswered. The data
presented in this study and in our companion paper (6) found little evidence for metabolites of AA mediating inhibition, enhancement, or the increase in activation kinetics. These results are
consistent with previous findings in mammalian neurons that, when
examined, the inhibitory actions of AA on whole cell Ca2+
currents appear independent of AA metabolism (16, 25, 44). However, these studies do not rule out an independent modulatory role
for AA metabolites since exogenously applied prostaglandin E2 can inhibit N-type currents in SCG neurons via a
membrane-delimited, G protein-coupled pathway (20). We
have ruled out a direct role for G proteins since GDP--S in the
pipette had no effect on any of the AA-induced changes in whole cell
currents described in this study. Whether protein kinases and/or
phosphatases play a role in mediating any of the actions of AA in SCG
neurons, as has been proposed for other cells (25, 33),
has not yet been examined.
The role of AA and its metabolites in cellular signaling has received increasing attention due to their ability to modulate a wide variety of ionic currents. The brain is particularly rich in AA-containing phospholipids. Stimulation of certain neurotransmitter receptors, a number of which are found in the SCG, as well as ischemic conditions increase the release of AA and its eicosanoid metabolites (3, 13, 14, 22-24). The characterization of the effects of AA on whole cell L- and N-type currents in SCG neurons in this and the companion report (6) raises the prospect that one of the primary mechanisms for neuronal Ca2+ current modulation is by receptor-mediated liberation of AA from membranes. Moreover, our data predict that, depending on the types of Ca2+ channels present in a cell type and the recording conditions used, the observed effect of AA modulation of Ca2+ currents could vary widely. Fatty acids, once released from neurons, have been hypothesized to play a role both in physiological and pathophysiological conditions, such as synaptic plasticity, ischemia/reperfusion-induced cell death, and seizures (1, 7, 43). Thus Ca2+ current modulation by AA may participate at the cellular level in changes in synaptic plasticity; this possibility awaits further investigation.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank John F. Heneghan, Thomas W. Honeyman, and Joshua J. Singer for reading various versions of the paper and H. Maurice Goodman and José Lemos for helpful discussion.
![]() |
FOOTNOTES |
---|
This publication was made possible by a Grant-In-Aid from the American Heart Association and a First Award from the National Institutes of Health.
A. R. Rittenhouse is a recipient of an Established Investigator Award from the American Heart Association.
Present address of C. F. Barrett: Dept. of Molecular and Cellular Physiology, Stanford University School of Medicine, Beckman Center, Stanford, CA 94305-5345.
Address for reprint requests and other correspondence: A. R. Rittenhouse, Room S4-221, Dept. of Physiology, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655 (E-mail: Ann.Rittenhouse{at}umassmed.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10 August 2000; accepted in final form 1 December 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abe, K,
Yoshidomi M,
and
Kogure K.
Arachidonic acid metabolism in ischemic neuronal damage.
Ann NY Acad Sci
559:
259-268,
1989[ISI][Medline].
2.
Ahern, DG,
and
Downing DT.
Inhibition of prostaglandin biosynthesis by eicosa-5,8,11,14 tetraynoic acid.
Biochim Biophys Acta
210:
456-461,
1970[ISI][Medline].
3.
Axelrod, J.
Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transdation.
Biochem Soc Trans
18:
503-507,
1990[ISI][Medline].
4.
Barlow, RB,
and
White RE.
Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity.
Am J Physiol Heart Circ Physiol
275:
H1283-H1289,
1998
5.
Barrett, CF,
and
Rittenhouse AR.
Modulation of N-type calcium channel activity by G-proteins and protein kinase C.
J Gen Physiol
115:
277-286,
2000
6.
Barrett, CF,
Liu L,
and
Rittenhouse AR.
Arachidonic acid reversibly enhances N-type calcium current at an extracellular site.
Am J Physiol Cell Physiol
280:
C1306-C1318,
2001
7.
Bazan, NG.
Arachidonic acid in the modulation of excitable membrane function and the onset of brain damage.
Ann NY Acad Sci
559:
1-16,
1989[ISI].
9.
Berridge, MJ.
Neuronal calcium signaling.
Neuron
21:
13-26,
1998[ISI][Medline].
10.
Capdevila, J,
Gil L,
Orellana M,
Marnett LJ,
Mason JI,
Yadagiri P,
and
Falck JR.
Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism.
Arch Biochem Biophys
261:
257-263,
1988[ISI][Medline].
11.
Chesnoy-Marchais, D,
and
Fritsch J.
Concentration-dependent modulations of potassium and calcium currents of rat osteoblastic cells by arachidonic acid.
J Membr Biol
138:
159-170,
1994[ISI][Medline].
12.
Colbert, MC,
and
Pan E.
Arachidonic acid reciprocally alters the availability of transient and sustained dendritic K+ channels in hippocampal CA1 pyramidal neurons.
J Neurosci
19:
8163-8171,
1999
13.
Dumuis, A,
Sebben M,
Haynes L,
Pin JP,
and
Bockaert J.
NMDA receptors activate the arachidonic acid cascade system in striatal neurons.
Nature
336:
68-70,
1988[ISI][Medline].
14.
Felder, CC,
Kanterman RY,
Ma AL,
and
Axelrod J.
Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis.
Proc Natl Acad Sci USA
87:
2187-2191,
1990[Abstract].
15.
Hamill, OP,
Marty A,
Neher E,
Sakmann B,
and
Sigworth EJ.
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patched.
Pflügers Arch
391:
85-100,
1981[ISI][Medline].
16.
Hatton, CJ,
and
Peers C.
Effects of cytochrome P-450 inhibitors on ionic currents in isolated rat type I carotid body cells.
Am J Physiol Cell Physiol
271:
C85-C92,
1996
17.
Hatton, CJ,
and
Peers C.
Arachidonic acid inhibits both K+ and Ca2+ currents in isolated type I cells of the rat carotid body.
Brain Res
787:
315-320,
1998[ISI][Medline].
18.
Hawrot, E,
and
Patterson PH.
Long-tern culture of dissociated sympathetic neurons.
Methods Enzymol
58:
574-584,
1979[Medline].
19.
Huang, JM,
Xian H,
and
Bacaner M.
Long-chain fatty acids activate calcium channels in ventricular myocytes.
Proc Natl Acad Sci USA
89:
6452-6456,
1992[Abstract].
20.
Ikeda, SR.
Prostaglandin modulation of Ca2+ channels in rat sympathetic neurons is mediated by guanine nucleotide binding proteins.
J Physiol (Lond)
458:
339-359,
1992[Abstract].
22.
Kanterman, RY,
Felder CC,
Brenneman DE,
Ma AL,
Fitzgerald S,
and
Axelrod J.
1-Adrenergic receptor mediates arachidonic acid release in spinal cord neurons independent of inositol phospholipid turnover.
J Neurochem
54:
1225-1232,
1990[ISI][Medline].
23.
Kanterman, RY,
Ma AL,
Briley EM,
Axelrod J,
and
Felder CC.
Muscarinic receptors mediate the release of arachidonic acid from spinal cord and hippocampal neurons in primary culture.
Neurosci Lett
118:
235-237,
1990[ISI][Medline].
24.
Katsuki, H,
and
Okuda S.
Arachidonic acid as a neurotoxic and neurotrophic substance.
Prog Neurobiol
46:
607-636,
1995[ISI][Medline].
25.
Keyser, DO,
and
Alger BE.
Arachidonic acid modulates hippocampal calcium current via protein kinase C and oxygen radicals.
Neuron
5:
545-553,
1990[ISI][Medline].
26.
Khurana, G,
and
Bennett MR.
Nitric oxide and arachidonic acid modulation of calcium currents in postganglionic neurones of avian cultured ciliary ganglia.
Br J Pharmacol
109:
480-485,
1993[Abstract].
29.
Liu, LW,
and
Rittenhouse AR.
Effects of arachidonic acid on unitary calcium currents in rat sympathetic neurons.
J Physiol (Lond)
525:
391-404,
2000
30.
Meves, H.
Modulation of ion channels by arachidonic acid.
Prog Neurobiol
43:
175-186,
1994[ISI][Medline].
31.
Mochizuki-Oda, N,
Negishi M,
Mori K,
and
Ito S.
Arachidonic acid activates cation channels in bovine adrenal chromaffin cells.
J Neurochem
61:
1882-1890,
1993[ISI][Medline].
32.
Nagano, N,
Imaizumi Y,
and
Watanabe M.
Modulation of calcium channel currents by arachidonic acid in single smooth muscle cells from vas deferens of the guinea-pig.
Br J Pharmacol
116:
1887-1893,
1995[Abstract].
33.
Petit-Jacques, J,
and
Hartzell HC.
Effect of arachidonic acid on the L-type calcium current in frog cardiac myocytes.
J Physiol (Lond)
493:
67-81,
1996[Abstract].
34.
Petrou, S,
Ordway RW,
Kirber MT,
Dopico AM,
Hamilton JA,
Walsh JV, Jr,
and
Singer JJ.
Direct effects of fatty acids and other charged lipids on ion channel activity in smooth muscle cells.
Prostaglandins Leukot Essent Fatty Acids
52:
173-178,
1995[ISI][Medline].
35.
Piomelli, D,
Volterra A,
Dale N,
Siegelbaum SA,
Kandel ER,
Schwartz JH,
and
Belardetti F.
Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells.
Nature
328:
38-43,
1987[ISI][Medline].
36.
Plummer, MR,
Logothetis DE,
and
Hess P.
Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons.
Neuron
2:
1453-1463,
1989[ISI][Medline].
37.
Plummer, MR,
Rittenhouse AR,
Kanevsky M,
and
Hess P.
Neurotransmitter modulation of calcium channels in rat sympathetic neurons.
J Neurosci
11:
2339-2348,
1991[Abstract].
38.
Rampe, D,
and
Lacerda AE.
A new site for the activation of cardiac calcium channels defined by the nondihydropyridine FPL 64176.
J Pharmacol Exp Ther
259:
982-987,
1991[Abstract].
39.
Regan, LJ,
Sah DWY,
and
Bean BP.
Ca2+ channels in rat central and peripheral neurons; high-threshold current resistant to dihydropyridine blocks and -conotoxin.
Neuron
6:
269-280,
1991[ISI][Medline].
40.
Richieri, GV,
Ogata RT,
and
Kleinfeld AM.
A fluorescently labeled intestinal fatty acid binding protein Interactions with fatty acids and its use in monitoring free fatty acids.
J Biol Chem
267:
23495-23501,
1992
41.
Roudbaraki, MM,
Drouhault R,
Bacquart T,
and
Vacher P.
Arachidonic acid-induced hormone release in somatotropes: involvement of calcium.
Neuroendocrinology
63:
244-256,
1996[ISI][Medline].
42.
Salari, H,
Braquet P,
and
Borgeat P.
Comparative effects of indomethacin, acetylenic acids, 15-HETE, nordihydroguaiaretic acid and BW755C on the metabolism of arachidonic acid in human leukocytes and platelets.
Prostaglandins Leukot Med
13:
53-60,
1984[ISI][Medline].
43.
Schacher, S,
Kandel ER,
and
Montaloro P.
cAMP and arachidonic acid simulate long-term structural and functional changes produced by neurotransmitters in Aplysia sensory neurons.
Neuron
10:
1079-1088,
1993[ISI][Medline].
44.
Schmitt, H,
and
Meves H.
Modulation of neuronal calcium channels by arachidonic acid and related substances.
J Membr Biol
145:
233-244,
1995[ISI][Medline].
45.
Shimada, T,
and
Somlyo AP.
Modulation of voltage-dependent Ca channel current by arachidonic acid and other long-chain fatty acids in rabbit intestinal smooth muscle.
J Gen Physiol
100:
27-44,
1992[Abstract].
46.
Skinner, J,
Sinclair C,
Romeo C,
Armstrong D,
Charbonneau H,
and
Rossie S.
Purification of a fatty acid-stimulated protein-serine/threonine phosphatase from bovine brain and its identification as a homolog of protein phosphatase 5.
J Biol Chem
272:
22464-22471,
1997
47.
Spector, AA.
Fatty acid binding to plasma albumin.
J Lipid Res
16:
165-179,
1975[Abstract].
48.
Striggow, F,
and
Ehrlich BE.
Regulation of intracellular calcium release channel function by arachidonic acid and leukotriene B4.
Biochem Biophys Res Commun
237:
413-418,
1997[ISI][Medline].
49.
Sumida, C,
Graber R,
and
Nunez E.
Role of fatty acids in signal transduction: modulators and messengers.
Prostaglandins Leukot Essent Fatty Acids
48:
117-122,
1993[ISI][Medline].
50.
Tobias, LD,
and
Hamilton JG.
The effect of 5,8,11,14-eicosatetraynoic acid on lipid metabolism.
Lipids
14:
181-193,
1979[ISI][Medline].
51.
Unno, T,
Komori S,
and
Ohashi H.
Some evidence against the involvement of arachidonic acid in muscarinic suppression of voltage-gated calcium channel current in guinea-pig ileal smooth muscle cells.
Br J Pharmacol
119:
213-222,
1996[Abstract].
52.
Vacher, P,
McKenzie J,
and
Dufy B.
Complex effects of arachidonic acid and its lipoxygenase products on cytosolic calcium in GH3 cells.
Am J Physiol Endocrinol Metab
263:
E903-E912,
1992[ISI][Medline].
53.
Villarroel, A.
Suppression of neuronal potassium A-current by arachidonic acid.
FEBS Lett
335:
184-188,
1993[ISI][Medline].
54.
Yamada, M,
Terzic A,
and
Kurachi Y.
Regulation of potassium channels by G-protein subunits and arachidonic acid metabolites.
Methods Enzymol
238:
394-422,
1994[ISI][Medline].
55.
Zhang, Y,
Cribbs LL,
and
Satin J.
Arachidonic acid modulation of 1H clone human T-type calcium channel.
Am J Physiol Heart Circ Physiol
278:
H184-H193,
2000