1 Program in Cellular and Molecular Physiology, 3 Program in Neuroscience, and 2 Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
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ABSTRACT |
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We examined the effects of arachidonic acid
(AA) on whole cell Ca2+ channel activity in rat superior
cervical ganglion neurons. Our companion paper (Liu L, Barrett CF, and
Rittenhouse AR. Am J Physiol Cell Physiol 280:
C1293-C1305, 2001) demonstrates that AA induces several
effects, including enhancement of current amplitude at negative
voltages, and increased activation kinetics. This study examines the
mechanisms underlying these effects. First, enhancement is rapidly
reversible by bath application of BSA. Second, enhancement appears to
occur extracellularly, since intracellular albumin was without effect
on enhancement, and bath-applied arachidonoyl coenzyme A, an
amphiphilic AA analog that cannot cross the cell membrane, mimicked
enhancement. In addition, enhancement is voltage dependent, in that
currents were enhanced to the greatest degree at 10 mV, whereas
virtually no enhancement occurred positive of +30 mV. We also
demonstrate that AA-induced increases in activation kinetics are
correlated with enhancement of current amplitude. An observed increase
in the voltage sensitivity may underlie these effects. Finally, the
majority of enhancement is mediated through N-type current, thus
providing the first demonstration that this current type can be
enhanced by AA.
calcium channel; eicosatetraynoic acid; fatty acids; arachidonoyl coenzyme A; voltage dependence
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INTRODUCTION |
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IN RAT SUPERIOR CERVICAL GANGLION (SCG) neurons, the polyunsaturated fatty acid arachidonic acid (AA; 20:4, n-6) is a potent inhibitor of Ca2+ channel activity. When unitary currents were elicited in cell-attached patches, using Ba2+ as the charge carrier, applying 5 µM AA led to a significant decrease in the activity of both L- and N-type Ca2+ channels (13). In our companion paper (12), we examined the effects of exogenous AA on whole cell currents in SCG neurons. In doing so, we discovered that AA induces several effects in addition to inhibiting L- and N-type currents. Consistent with inhibition, AA increased holding potential-dependent inactivation, in agreement with our observation that AA increases the occurrence of null sweeps in cell-attached patch recordings of single L- and N- type Ca2+ channels (13). In addition, AA increased the rate of whole cell current activation. This effect was largely selective for N-type Ca2+ channels and was independent of G protein activity.
AA also induced a significant increase in current amplitude at negative voltages (12). This enhancement could be separated from inhibition, since dialyzing the cell with bovine serum albumin (BSA), a protein that can bind fatty acids (19), blocked the majority of inhibition but was without effect on enhancement. Finally, as with both inhibition and faster activation, enhancement is independent of G protein activity.
Although AA-induced enhancement of Ca2+ currents has been
reported in other preparations (5, 8, 22), this effect has not been observed previously in neurons. Because Ca2+ entry
through neuronal voltage-gated Ca2+ channels can play an
important role in coordinating electrical signaling with cellular
processes like neurotransmitter release and enzyme activation (3,
17), a pathway that induces enhanced Ca2+ influx in
neurons is of particular interest. Therefore, the purpose of this study
was to examine the mechanism and properties of AA-induced enhancement
of Ca2+ currents in SCG neurons. In this report, we present
the first evidence that AA reversibly enhances whole cell N-type
current by a mechanism distinct from its inhibitory effects on L- and N-type currents. This effect is voltage dependent, with the greatest enhancement observed at 10 mV. In addition, enhancement does not
require AA metabolism, and appears to be mediated extracellularly. Finally, our results indicate that the mechanism of AA-induced enhancement involves both an increase in activation rate and an increase in voltage sensitivity. Together with the accompanying paper
(12), our findings add to the growing body of evidence that AA can exert a diverse range of effects on neuronal
Ca2+ currents.
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METHODS |
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Preparation and culture of SCG neurons. Following decapitation, the SCG were removed from 1- to 4-day-old Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA), and neurons were dissociated by trituration through a 22-gauge, 1.5-in. needle. Following dissociation, cells were plated on poly-L-lysine-coated glass coverslips in 35-mm culture dishes and incubated at least 4 h before recording (7). Cells were maintained in 5% CO2 at 37°C, in DMEM supplemented with 7.5% fetal bovine serum, 7.5% calf serum, 100 IU/ml penicillin, 0.1 mg/ml streptomycin, 4 mM L-glutamine (all from Sigma Chemical, St. Louis, MO), and 0.2 µg/ml nerve growth factor (Bioproducts for Science, Indianapolis, IN); cells were used within 12 h of preparation. Spherical neurons lacking visible processes were selected for recording.
Preparation and culture of tsA201 cells.
The simian virus 40 (SV40) large T antigen-transformed HEK-293 subclone
tsA201, transfected to stably express the rat N-type Ca2+
channel 1B-a splice variant (
A415/
SFMG/+ET; see
Table 2 in Ref. 10) together with rat neuronal-derived
3 and
2/
-1 subunits, was a generous
gift from Y. Lin and D. Lipscombe (Brown University; Ref.
9). Cells were maintained in 5% CO2 at 37°C
in DMEM supplemented with 10% fetal bovine serum, 4 mM
L-glutamine, 1× antibiotic-antimycotic (100 IU/ml
penicillin, 0.1 mg/ml streptomycin, and 0.25 µg/ml amphotericin B;
GIBCO BRL, Rockville, MD), 25 µg/ml Zeocin (Invitrogen, Carlsbad,
CA), and 5 µg/ml Blasticidin (Invitrogen). For recording, semiconfluent cells were trypsinized, plated on
poly-L-lysine-coated glass coverslips, and cultured for at
least 1 h before recording. Cells were used for recording within
6 h of preparation.
Electrophysiology.
Ba2+ currents were recorded at room temperature
(20-24°C) using the whole cell configuration of an Axopatch 200B
patch-clamp amplifier (Axon Instruments, Foster City, CA). Except where
noted, voltage steps of 100 ms duration were applied every 4 s
from a holding potential of 90 mV. Currents were passed through the amplifier's four-pole low-pass Bessel filter set at 2 kHz, then digitized at 20 kHz with a 1401plus interface (Cambridge
Electronic Design, Cambridge, UK). Data were collected using the Patch
software suite, version 6.3 (Cambridge Electronic Design) and stored on a personal computer. Before analysis, capacitive and leak currents were
subtracted using a scaled-up current elicited with a test pulse to
115 mV. Recording pipettes were pulled from borosilicate capillary
tubes (Drummond Scientific, Broomall, PA; #2-000-210) and heat polished
just before use; when filled with internal solution, pipette resistance
ranged from 2.5 to 3 M
. Drugs were applied via gravity-driven bath
perfusion, with an estimated time to complete bath exchange of
5-10 s. For SCG experiments using the irreversible N-type
Ca2+ channel blocker
-conotoxin GVIA (
-CgTx), cells
were placed in Tyrode solution (145 mM NaCl, 5.4 mM KCl, 10 mM HEPES,
pH 7.5) containing 1 µM
-CgTx for at least 10 min before
recording. Recording solutions containing dihydropyridines were
protected from light until use.
Pharmacology.
AA was obtained from Nu-Check-Prep (Elysian, MN). GDPS was obtained
from either Research Biochemicals (Natick, MA) or Sigma Chemical.
-CgTx was from Bachem Bioscience (King of Prussia, PA), and
(+)-202-791 was a gift from Sandoz Pharmaceuticals (Sandoz, Switzerland). FPL-64176 and nimodipine (NMN) were both obtained from
Research Biochemicals. Except where noted, all other chemicals and
reagents were obtained from Sigma Chemical.
Data analysis.
Analysis software included the Patch software suite, version 6.3 (Cambridge Electronic Design), and Origin 5.0 (Microcal Software, Northampton, MA). Data are presented as means ± SE where
applicable. Statistical significance was determined using a two-way
paired or unpaired t-test, as appropriate. Sample size
(n) represents the number of cells recorded under each
condition. Percent inhibition and percent enhancement were calculated
by the equations [1 (Idrug/Icon)]100 and
[(Idrug/Icon)
1]100, respectively, where Idrug is the current
amplitude measured at a given time after drug application, and
Icon is the current amplitude before drug application. The Boltzmann fits of the activation data presented in
Fig. 5D were calculated using the equation
I/Imax = {(I1
I2)/[1 +
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RESULTS |
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AA-induced enhancement and inhibition of whole cell
Ba2+ currents follow distinctly different
time courses.
The first step in our analysis was to test whether current enhancement
by AA is mediated at a site different from inhibition. If enhancement
and inhibition are mediated at the same site, then these effects should
develop along a similar time course. Therefore, in the same recording,
we applied alternating test pulses to +10 and 10 mV, to monitor
inhibition and enhancement, respectively (Fig.
1, A and B). Both
inhibition and enhancement were then fit to single-exponential
time constants (Fig. 1C). Bath application of 5 µM AA led
to a rapid increase in current amplitude at both voltages (Fig.
1A); this increase was observed in six of six recordings. However, after the initial increase in amplitude, currents elicited at
+10 mV then began to decrease (Fig. 1A), with a mean time
constant of 4.30 ± 0.51 min (Fig. 1C). Thus, after 5 min, the overall effect of AA on currents elicited at +10 mV was an
inhibition of 40.5 ± 9.7% (see Figs. 1D and
12A). In contrast, enhancement of currents elicited at
10
mV occurred with a mean time constant of 0.69 ± 0.10 min (Fig.
1C); after 5 min, AA enhanced current amplitude at
10 mV
by 155.5 ± 28.1% (see Figs. 1D and 12B).
These results demonstrate that enhancement develops significantly
faster than inhibition, providing evidence that AA may have separate
sites of action for these two effects.
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Enhancement of whole cell current amplitude by AA is
reversible.
AA-induced inhibition was largely reversed by bath application of BSA
(12, 13). In this study, we employed a similar approach to
determine whether enhancement is also reversible. We first examined
whether enhancement could be reversed by washing control solution
(without BSA) into the recording chamber. Washing with control solution
for 1 min reversed 24.6 ± 8.2% of AA-induced enhancement
(n = 3). Although significant (P < 0.05), this reversal was far from complete. Therefore, 0.5 mg/ml BSA
was added to the wash solution. A typical time course is shown in Fig.
2A. After 1 min in AA, the
introduction of wash solution containing BSA rapidly reduced current
amplitude to control levels. AA's effect on current amplitude at 10
mV, and its reversibility by BSA, are summarized in Fig. 2C.
Washing out AA with BSA reversed 97.2 ± 6.1% of AA-induced
enhancement (n = 6).
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AA-induced enhancement occurs extracellularly.
The observation that intracellular BSA was without effect on AA-induced
enhancement suggests that this effect may be mediated from the outside
of the cell. To test this, we applied the fatty acid analog palmitoyl
coenzyme A (PCoA), which contains a negatively charged moiety that
prevents "flipping" across cell membranes (4), to the
bath. This molecule has been shown previously to mimic the effects of
AA in increasing the activity of potassium channels in smooth muscle
cells (16). In SCG neurons, bath application of 10 µM
PCoA led to a rapid, sustained enhancement of current amplitude (Fig.
3A). This enhancement was over
a narrow range of test potentials, with significant enhancement
observed at 0 mV (Fig. 3, B and C), providing
evidence that fatty acid-induced enhancement is voltage dependent. In
addition, unlike AA, PCoA caused no inhibition of current amplitude at
any voltage tested, suggesting that inhibition is likely mediated from
the cytoplasmic side, consistent with our intracellular BSA data.
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Enhancement does not require AA metabolism. Modulation of ion currents by AA can occur either by direct interaction with the channels or indirectly by a downstream pathway, sometimes involving the generation of biologically active AA metabolites (for review, see Refs. 14 and 15). However, there are several arguments against an AA metabolite mediating enhancement of Ba2+ currents in SCG neurons. First, enhancement was observed even in the presence of intracellular BSA, a condition that should prevent AA metabolism. Moreover, its immediate onset, rapid development, and rapid reversibility suggest that enhancement might be mediated directly by AA. Finally, the fatty acid analogs PCoA and ACoA, which are unable to enter the cell, mimicked AA-induced enhancement of current amplitude. Therefore, it is highly unlikely that enhancement of current involves AA metabolism.
Despite these arguments, we could not, based on our experiments thus far, exclude the possibility that enhancement involves an AA metabolite. Therefore, to address this possibility, we examined the effect of ETYA, an AA analog that cannot be metabolized by the three common pathways (the lipoxygenase, cyclooxygenase, and epoxygenase pathways) known to generate biologically active products (20, 21). Bath application of 30 µM ETYA led to a rapid, sustained enhancement of whole cell current amplitude (Fig. 4, A and B). As with PCoA and ACoA, this enhancement was voltage dependent (Fig. 4, C and D). ETYA caused no significant inhibition at any voltage tested, consistent with the results in our companion paper (12). These findings support the hypothesis that AA-induced enhancement of current amplitude does not require metabolism. Moreover, because ETYA mimics enhancement, but not inhibition, these results provide further evidence that these two effects are likely mediated by distinct mechanisms.
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AA increases the voltage dependence of activation.
In our companion paper (12), we examined the effect of AA
on voltage-dependent activation. Consistent with AA's effects on
current amplitude, application of AA for 5 min induced a slight increase in normalized tail current amplitude at negative voltages. However, possibly due to the influence of inhibition in the presence of
AA, no significant change in voltage-dependent activation was noted.
Therefore, we investigated the effect of AA on activation under
recording conditions designed to maximize enhancement and minimize
inhibition: 0.5 mg/ml BSA was included in the pipette solution, and the
effect of 5 µM AA was examined at 1 min. We first measured the whole
cell current-voltage (I-V) relationship under these
recording conditions before and after application of AA. Currents were
elicited by applying 200-ms voltage ramps from 60 to +80 mV. Figure
5A shows that application of
AA increased current amplitude between
30 and +30 mV, but was without
effect on the reversal potential.
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AA-induced enhancement is associated with faster activation. In our examination of AA's effects on whole cell currents elicited at +10 mV, we observed that, in addition to changing current amplitude, AA appeared to cause an increase in the rate of activation at this voltage (12). This increase in activation is not likely associated with inhibition, since, in cell-attached patch recordings, channels inhibited by AA exhibited increased first latency (13). Nevertheless, we explored whether this effect occurs in association with either inhibition or enhancement.
Whole cell activation was examined by normalizing inward current at each time point to the peak inward current obtained during a 100-ms voltage step to +10 mV. Normalized data from several experiments were then averaged for each condition (Fig. 6). Figure 6A shows that bath application of 5 µM AA for 1 min led to a significant increase in the rate of activation. Because AA-induced enhancement of current amplitude appears to reach steady-state within ~1 min, whereas inhibition takes several minutes to reach steady-state (see Fig. 1, A and C), we tested whether the increase in activation rate also reached steady state within 1 min. Activation was therefore examined after treatment for 5 min with AA for comparison (Fig. 6B). At 5 min, the rate of activation was not noticeably different from at 1 min, as the two curves superimposed (compare the AA curves in Fig. 6, A and B). Therefore, as with enhancement, AA-induced changes in activation reached steady state within 1 min, suggesting that increased activation kinetics may be associated with enhancement, rather than inhibition.
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AA enhances N-type current.
Our analysis of AA's effects revealed that the majority of increased
activation kinetics is selective for N-type current, as it was still
observed in the presence of the L-type Ca2+ channel
antagonist NMN, but was largely lost when cells were pretreated with
the N-type Ca2+ channel blocker -CgTx (12).
Given that this effect appears to be associated with AA-induced
enhancement, it seems likely that enhancement should be mediated, at
least in part, by N-type current. Therefore, if AA enhances N-type
current, then application of AA, in the continued presence of NMN,
should still lead to enhancement. Bath application of 5 µM AA, in the
presence of 1 µM NMN, led to an initial enhancement of current
amplitude at both
10 and +10 mV (Fig.
8A; n = 7). As
observed in the absence of NMN, currents elicited at +10 mV began to
decrease after ~1 min, leading to a net result of significant
inhibition after treatment for 5 min with AA (see Fig. 12A).
Also, as seen in the absence of NMN, the enhancement observed at
10
mV was sustained throughout the recording (see Figs. 8 and
12B). AA-induced enhancement at
10 mV, in the presence of
NMN, was 92.9 ± 22.7%, compared with 155.5 ± 28.1% in the
absence of NMN (see Fig. 12B). This decreased level of
enhancement observed in the presence of NMN raises the possibility that
NMN-sensitive (e.g., L-type) current may also be enhanced by AA.
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L-type Ca2+ channel agonists do not preclude AA-induced enhancement. Our lab previously presented whole cell I-V plots generated before and several minutes after bath application of AA, in the continued presence of (+)-202-791 (see Ref. 13). Under those conditions, the dominant observed effect of AA was an inhibition of current amplitude; no AA-induced enhancement was observed at any voltage, suggesting that the presence of (+)-202-791 may have precluded AA-induced enhancement. Since the data in the present study indicate that the presence of L-type Ca2+ channel ligands should not affect AA-induced enhancement, we sought to resolve this discrepancy.
The I-V plots presented by Liu and Rittenhouse (13) represented data collected in control solution and again after at least 7 min of AA treatment. Thus, if enhancement did initially occur, but was then offset by inhibition, this would not be observed simply by comparing I-V plots. Therefore, in addition to I-V plots, we also examined time courses of current amplitude during application of AA in the continued presence of L-type Ca2+ channel agonists. When whole cell currents were elicited in the continued presence of 1 µM (+)-202-791, bath application of 5 µM AA had an initial effect similar to that observed without an agonist: currents elicited at both +10 and
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DISCUSSION |
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In the accompanying paper (12), we presented evidence that exogenous AA induces several effects on whole cell Ba2+ currents in neonatal rat SCG neurons, including inhibition of both L- and N-type currents and increased holding potential-dependent inactivation. AA also induces faster activation kinetics, largely selective for N-type current. Finally, we found that application of AA causes an enhancement of whole cell current amplitude. This enhancement appeared distinct from inhibition, as including BSA in the pipette solution reduced inhibition but did not affect enhancement. The purpose of this study was to investigate the mechanism and properties of this enhancement.
Our results show that AA reversibly enhances N-type current
by inducing an increase in voltage-dependent activation, as well as an
increase in activation kinetics. Blocking L-type current with NMN did
not affect AA's capacity to enhance current amplitude, suggesting that
the remaining current type is enhanced by AA. Moreover, when cells were
pretreated with the irreversible N-type Ca2+ channel
blocker -CgTX, most, but not all AA-induced enhancement was
abolished, also raising the possibility that AA may enhance non-N-type
current. This is consistent with our finding that AA induced a lower
level of enhancement in the presence of NMN. Finally, when AA was
applied to tsA201 cells expressing recombinant N-type channels,
currents elicited at negative voltages increased in amplitude to the
same degree as SCG neurons recorded under similar conditions.
Because AA-induced enhancement is mediated, for the most part, through
N-type channels, then AA, in the continued presence of L-type channel
agonists, should still cause an enhancement at negative voltages; i.e.,
the agonist's effects and AA-induced enhancement should sum. Our data
demonstrate exactly that: AA caused the same increase in current
amplitude at 10 mV whether the L-type channel agonist (+)-202-791 was
present or not. In addition, the enhanced current elicited in the
presence of (+)-202-791 decreased over time, possibly explaining why,
in the presence of L-type Ca2+ channel agonists, no
apparent change in current amplitude was observed at negative voltages
after several minutes in AA (13).
Our findings suggest that AA has at least two distinct sites of action, one mediating inhibition and one mediating enhancement. Dialyzing the cytoplasm with BSA largely blocked AA-induced inhibition but was without effect on either the magnitude or rate of enhancement. In addition, bath-applied PCoA and ACoA, which cannot cross the cell membrane, each caused enhancement but not inhibition.
AA-induced enhancement of Ca2+ currents has been observed in GH3/B6 pituitary cells (22), rat osteoblasts (5), and guinea pig ventricular myocytes (8). In pituitary cells and osteoblasts, this enhancement was voltage dependent. When we examined enhancement in SCG neurons, we found that enhancement of Ba2+ currents by AA in SCG currents also is voltage dependent.
Under our recording conditions, AA-induced enhancement of whole cell currents was most readily observed at negative test potentials. In addition, at voltages more positive than 0 mV, where neuronal Ca2+ currents are often examined, inhibition became the dominant effect over time, thus occluding enhancement. Finally, our analysis suggests that AA appears to enhance N-type current to the greatest degree. Taken together, these findings may explain why AA-induced enhancement of currents has not been previously identified in other neuronal preparations.
In ventricular myocytes, L-type current appeared to reach peak more rapidly after AA treatment than control (8), consistent with AA-induced faster activation. In contrast, no change in activation kinetics was noted in association with AA-induced enhancement of low-voltage-activated Ca2+ currents in GH3/B6 pituitary cells (22) or rat osteoblasts (5), although this property was not directly examined. In neurons, changes in activation kinetics could have a profound influence on Ca2+ influx, which could in turn influence excitability. Therefore, it was important to determine whether the increased activation kinetics observed in SCG neurons is a component of AA-induced inhibition or enhancement. Our results indicate that increased activation is not associated with inhibition, consistent with cell-attached patch recordings of unitary Ca2+ channels, in which AA increased first latency (13). However, our findings do support the conclusion that increased activation is a component of AA-induced enhancement, as the development of both effects was strongly correlated.
Changes in surface charge can sometimes lead to changes in ion channel permeation and gating (6, 23). Therefore, fatty acid-induced enhancement might be the result of altered surface charge. This is unlikely because the coenzyme A head groups of PCoA and ACoA contain several negative charges, whereas ETYA and AA lack these charges. Although these compounds contain different charges, they induce a similar effect on whole cell currents. In addition, we would predict that changes in surface charge should occur very rapidly following perfusion of the recording chamber. In contrast, enhancement of current amplitude by AA occurred with a time constant of ~41 s, too slowly to be accounted for by a surface charge effect.
AA can be liberated from cell membrane phospholipids by several pathways (2). G protein-coupled receptors can activate phospholipases, which in turn can catalyze the release of AA (1). A number of neurotransmitters can activate receptor-mediated AA liberation (1), and SCG neurons are known to express receptors for these agonists, including muscarinic receptors (11, 18). Therefore, trans-synaptic stimulation of these neurons may lead to diverse modulation of Ca2+ currents by AA.
Together with our accompanying paper (12), we show that AA can induce several effects on Ca2+ currents in sympathetic neurons. Which effects may be induced may depend on the source of AA and the length of exposure to AA. Our results suggest that a brief external exposure to AA may be sufficient to enhance Ca2+ influx, even with very brief depolarizations, thereby potentiating neuronal excitability. In contrast, exposure to intracellular AA may lead to inactivation of Ca2+ channels, which would inhibit excitability.
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ACKNOWLEDGEMENTS |
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We thank Drs. Diane Lipscombe and Yingxin Lin for generously providing the tsA201 cell line expressing rat sympathetic N-type Ca2+ channels. We thank Drs. Alex Dopico, Thomas W. Honeyman, José Lemos, and Joshua J. Singer for helpful discussions and critical reading of this manuscript.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grant NS-34195 and American Heart Association Grant 9940225. Its contents are the responsibility of the authors and do not necessarily reflect the official view of these granting agencies.
A. R. Rittenhouse is the recipient of an Established Investigator Award from the American Heart Association.
Address for reprint requests and other correspondence: A. R. Rittenhouse, Rm. 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 13 November 2000.
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