© 2000 American Heart Association, Inc.
Cellular Biology |
Roles of Mitogen-Activated Protein Kinases and Protein Kinase C in 
1A-Adrenoceptor–Mediated Stimulation of the Sarcolemmal Na+-H+ Exchanger
From the Centre for Cardiovascular Biology and Medicine, King’s College London, London, UK.
Correspondence to Dr Metin Avkiran, Cardiovascular Research, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK. E-mail metin.avkiran{at}kcl.ac.uk
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Abstract |
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Abstract—Activation of the sarcolemmal Na+-H+ exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of
1-adrenoceptor (AR)
stimulation. Although such regulation of sarcolemmal NHE activity has
been shown to be selectively mediated through the 1A-AR
subtype, distal signaling mechanisms remain poorly defined. We
investigated the roles of various kinase pathways in
1A-AR–mediated stimulation of sarcolemmal NHE activity
in adult rat ventricular myocytes. As an index of NHE
activity, trans-sarcolemmal acid efflux rate
(JH) was determined through
microepifluorescence in single cells, during recovery from
intracellular acidosis in bicarbonate-free conditions. Extracellular
signal-regulated kinase (ERK), p38-mitogen-activated protein
kinase (MAPK), and p90rsk activities were indexed on the
basis of analysis of their phosphorylation
status. In control cells, there was no change in
JH in response to vehicle.
Phenylephrine and A61603, an 1A-AR
subtype–selective agonist, increased JH, as
well as cellular ERK and p90rsk activities. Neither agonist
affected p38 activity, which was increased with sorbitol. The MAPK
kinase inhibitor PD98059 abolished
phenylephrine- and A61603-induced increases in
JH and cellular ERK and p90rsk
activities. In contrast, the PKC inhibitor GF109203X
abolished phenylephrine- and A61603-induced increases in
JH but failed to prevent the increases in
ERK and p90rsk activities. Our findings suggest that
1A-AR–mediated stimulation of sarcolemmal NHE activity
in rat ventricular myocytes requires activation of the ERK
(but not the p38) pathway of the MAPK cascade and that the ERK-mediated
effect may occur via p90rsk. Activation of PKC is also
required for 1A-AR–mediated NHE stimulation, but such
regulation occurs through an ERK-independent pathway.
Key Words: Na+-H+ exchange • receptors, adrenergic • signal transduction • protein kinases
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The sarcolemmal Na+-H+ exchanger (NHE) consists of the ubiquitous NHE-1 isoform of the multigene NHE family1 and is an important H+ extrusion mechanism that contributes to the integrated control of intracellular pH (pHi) in cardiac myocytes.2 Although sarcolemmal NHE activity is regulated primarily by pHi and is markedly increased in response to acidosis,2 it is also subject to modulation by several stimuli that act via Gq protein–coupled receptors (GqPCRs), such as
1-adrenergic agonists,3
endothelin,4 thrombin,5 and
angiotensin II.6 These stimuli increase
sarcolemmal NHE activity by enhancing the affinity of the exchanger for
intracellular H+, which is the primary mechanism
underlying receptor-mediated regulation of NHE-1.7
Of the various GqPCR signaling pathways that
regulate sarcolemmal NHE activity, those that are activated by
1-adrenoceptors
(1-ARs) warrant attention because they are
likely to mediate important physiological and
pathophysiological responses. In this regard,
increased sarcolemmal NHE activity and consequent increases in
pHi, intracellular Na+, or
both have been suggested to be causally involved in the positive
inotropic,8 arrhythmogenic,9 and
hypertrophic10 11 consequences of myocardial
1-AR stimulation. Furthermore,
1-AR–mediated stimulation of sarcolemmal NHE
activity may contribute to the antiacidotic effect during
ischemia of ischemic or pharmacological
preconditioning.12 In an effort to delineate the molecular
mechanisms that underlie 1-adrenergic
stimulation of sarcolemmal NHE activity, we recently demonstrated that
such regulation of the exchanger is mediated selectively through the
1A-AR subtype.13 Nevertheless,
pertinent signaling pathways distal to the GqPCR
remain controversial (eg, see Wallert and Fröhlich3
versus Pucéat et al14 on the role of protein kinase
C [PKC]) and incompletely characterized.
The results of recent studies in noncardiac cells suggest that
intracellular signals transduced via the extracellular signal-regulated
kinase (ERK)15 16 17 and p3818 pathways of the
mitogen-activated protein kinase (MAPK) cascade may be
important contributors to GqPCR-mediated
regulation of NHE-1 activity. Furthermore, GqPCR
(including 1-AR) stimulation has been shown to
activate both ERK and p38 in isolated rat hearts19
and cultured neonatal rat ventricular
myocytes,20 21 through mechanisms that may involve
PKC.21 22 However, the potential roles and interactions of
ERK, p38, and PKC in 1A-AR–mediated
regulation of sarcolemmal NHE activity have not been investigated.
The present study was undertaken to determine the involvement of
ERK, p38, and PKC pathways in 1A-AR–mediated
stimulation of sarcolemmal NHE activity in freshly isolated adult rat
ventricular myocytes. To achieve this, we used established
techniques for the determination of NHE and various kinase activities,
in conjunction with 2 agonists of distinct
1-AR subtype selectivity and specific kinase
inhibitors. Our data suggest that
1A-AR–mediated stimulation of sarcolemmal NHE
activity in adult rat ventricular myocytes requires
activation of the ERK (but not the p38) pathway of the MAPK cascade.
Activation of PKC is also required for this response, but PKC and ERK
appear to be independent regulators of NHE activity in response to
1A-AR stimulation.
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Materials and Methods |
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This investigation was performed in accordance with the Home Office "Guidance on the Operation of the Animals (Scientific Procedures) Act 1986," published by HMSO (London).
Isolation of Ventricular Myocytes
Ventricular myocytes were isolated from the hearts
of adult male Wistar rats (weight 200 to 250 g) through enzymatic
digestion for the study of drug effects on sarcolemmal
NHE5 6 13 23 or cellular kinase6
activity.
Determination of Sarcolemmal NHE Activity
Sarcolemmal NHE activity was determined in single myocytes
loaded with the pH-sensitive fluoroprobe cSNARF-1, through the use of a
microepifluorescence technique.5 6 13 23 Cells
were maintained in bicarbonate-free medium (34°C) throughout each
experiment, thus enabling the rate of acid efflux
(JH) to be used as the indicator of
sarcolemmal NHE activity. To quantify drug-induced changes in NHE
activity, JH values were determined at
pHi intervals of 0.05 during recovery from
intracellular acidosis.
Determination of Cellular MAPK and p90rsk
Activities
MAPK activities were determined through the detection of dual
phosphorylation of ERK1/2 and p38 on the Thr and Tyr
residues of their regulatory Thr-Xaa-Tyr motifs, by Western
analysis with dual phosphospecific antibodies (New England
Biolabs).6 The activity of p90rsk
was determined through the detection of Ser381
phosphorylation with a phosphospecific antibody (New
England Biolabs). To confirm equal protein loading, we used
nonphosphospecific antibodies for ERK2 (Santa Cruz Biotechnology), p38
(Santa Cruz Biotechnology), and p90rsk
(Transduction Laboratories). Specific protein bands were detected with
enhanced chemiluminescence and autoradiography, and
phosphorylation status was quantified with laser
densitometry.
Experimental Protocols
For the determination of drug effects on NHE activity, myocytes
(10 per group, obtained from 7 to 9 separate hearts in each protocol)
were subjected to intracellular acidosis through transient (3 minutes)
exposure to 20 mmol/L NH4Cl (first acid
pulse), which was repeated 
15 minutes later (second acid
pulse).5 6 13 In control cells, both acid pulses occurred
in the absence of any drug. When the effects of
phenylephrine (Sigma), a non–subtype-selective
1-AR agonist, or A61603 (gift from Abbott
Laboratories), an 1A-AR subtype–selective
agonist, were studied, this was present during the second pulse.
When the effects of either agonist in the presence of the MAPK kinase
(MEK) inhibitor PD98059 (Calbiochem-Novabiochem) or the PKC
inhibitor GF109203X (Calbiochem-Novabiochem) were studied,
the inhibitor was present from 10 minutes before the
second acid pulse. Drug vehicles were included in superfusion
solutions, as appropriate. For determination of the effects on kinase
activity, myocytes in suspension were exposed to the same drugs with
the use of identical concentrations and exposure times (4 experiments
with each protocol, with cells from 4 separate hearts).
Statistical Analysis
Values are given as mean±SEM. Experiments in each
microepifluorescence protocol were randomized, with
contemporary controls. A paired t test was used to assess
changes in JH between the first and second
acid pulses. For an intergroup comparison of the change in
JH at pHi 6.90
(
JH6.9) or of protein kinase
phosphorylation, data were subjected to ANOVA; further
analysis was made with Dunnett’s test to compare each
treatment group with the control group. P<0.05 was
considered significant.
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Results |
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Role of ERK1/2 in
1A-AR–Mediated Stimulation of
Sarcolemmal NHE ActivityFigure 1
shows the
JH-versus-pHi
relationships obtained after 2 consecutive acid pulses in the 6 groups
of this protocol, which addressed the role of ERK1/2 in
1A-AR–mediated stimulation of sarcolemmal NHE
activity. During the second acid pulse, control cells (Figure 1A) continued to receive agonist-free superfusate,
whereas the other groups were exposed to phenylephrine
(Figure 1B) or A61603 (Figure 1C) in the absence or
presence of PD98059. The concentrations of phenylephrine
and A61603 were selected on the basis of our dose-response
studies13 and were those that produced near-maximal
stimulation of sarcolemmal NHE activity. In control cells, the
JH-versus-pHi curves
obtained after both acid pulses were superimposed (Figure 1A, left), indicating that temporal changes in NHE activity do not occur in
the absence of drug exposure. In these cells, PD98059 alone had no
effect on the
JH-versus-pHi curve
(Figure 1A, right). Consistent with our previous data
that 1A-AR stimulation increases sarcolemmal
NHE activity,13 phenylephrine and A61603
both produced rightward shifts of the
JH-versus-pHi curve
such that over the range of pHi 6.80 to 7.20,
JH was significantly greater in the
presence of either agonist (Figures 1B and 1C, left). However,
in the presence of PD98059, neither phenylephrine nor
A61603 produced a significant shift in the
JH-versus-pHi curve
(Figures 1B and 1C, right). Figure 3A shows
JH6.9 values in the 6 study groups and
allows a comparison of the effects of the different stimuli on
sarcolemmal NHE activity. As illustrated, in the absence of PD98059,
JH6.9 was significantly greater in cells
that received phenylephrine or A61603. In contrast, in the
presence of PD98059, there was no significant difference in
JH6.9 between control cells and those
exposed to either 1-AR agonist. Because
PD98059 inhibits Raf-mediated activation of MEK1/2,24
which in turn activates ERK1/2,25 these data
suggest that activation of the ERK pathway is a necessary step in
1A-AR–mediated stimulation of sarcolemmal NHE
activity.
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) and second (•) acid pulses are shown in control
cells (A) and in cells exposed to 10 µmol/L
phenylephrine (B) or 30 nmol/L A61603 (C) during second
pulse in absence or presence of MEK inhibitor PD98059
(50 µmol/L) (10 cells per group, obtained from 7 hearts).
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Role of PKC in 1A-AR–Mediated Stimulation of
Sarcolemmal NHE Activity
Figure 2 shows the
JH-versus-pHi
relationships obtained in this protocol, which was analogous to that
described earlier except that it tested the role of the PKC pathway. In
control cells, the
JH-versus-pHi curves
obtained after both acid pulses were again superimposed (Figure 2A, left). GF109203X had no effect on the
JH-versus-pHi curve
in control cells (Figure 2A, right) but abolished the rightward
shifts of the curve induced by phenylephrine (Figure 2B) or A61603 (Figure 2C). As illustrated in Figure 3B
, in the absence of GF109203X,
JH6.9 was again significantly greater in
cells that received phenylephrine or A61603, reflecting
1A-AR–mediated stimulation of sarcolemmal NHE
activity. In contrast, in the presence of GF109203X, there was no
significant change in JH6.9 in response
to either 1-AR agonist. Because GF109203X is a
selective inhibitor of PKC,26 these data
suggest that PKC is a critical component of the distal signaling
pathways of the 1A-AR that mediate the
stimulation of sarcolemmal NHE activity.
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Regulation of Sarcolemmal NHE Activity via PKC and ERK1/2:
Contiguous or Independent Pathways?
These data suggest that in
1A-AR–mediated stimulation of sarcolemmal NHE
activity, both PKC and ERK1/2 are critical components of the signaling
pathways distal to the GqPCR. This situation
could arise if (1) PKC and ERK1/2 are proximal and distal components of
a contiguous signaling pathway or (2) PKC and ERK1/2 mediate
independent signaling pathways, but activation of both is necessary to
achieve the full response. To address this issue, we determined the
effects on ERK activity of 1-AR stimulation in
the absence or presence of GF109203X. Figure 4 shows that in parallel with their
effects on sarcolemmal NHE activity, phenylephrine and
A61603 produced significant increases in ERK activity. GF109203X failed
to prevent significant increases in ERK activity in response to
phenylephrine and A61603, whereas PD98059 abolished ERK
activation by each agonist. The distinct effects of the 2 kinase
inhibitors on ERK activation (Figure 4), despite
their common ability to prevent
1A-AR–mediated stimulation of sarcolemmal NHE
activity (Figure 3), allow the following conclusions to be made:
(1) in adult rat ventricular myocytes,
1-AR–mediated activation of ERK1/2 occurs, to
a large extent, through PKC-independent mechanisms, and (2)
activation of both pathways is required for
1A-AR–mediated stimulation of sarcolemmal NHE
activity.
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The lack of an effect of GF109203X on ERK activation might
reflect the absence of PKC-mediated ERK regulation or the dissociation
of such regulation from the 1-AR–mediated
response. To address this issue, we determined the effects on ERK
activity of direct PKC activation by phorbol
12-myristate 13-acetate (PMA). As shown in Figure 5, PMA produced a significant increase in
ERK activity, indicating that PKC-mediated ERK activation is functional
in adult rat ventricular myocytes. Figure 5 also
shows that GF109203X abolished PMA-induced ERK activation, thus
confirming that the concentration used was sufficient to block
PKC-mediated responses.
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Role of p38 in 1A-AR–Mediated Stimulation of
Sarcolemmal NHE Activity
In some cardiac preparations,19 21
1-AR stimulation has been shown to
activate p38, which has been implicated in
GqPCR-mediated regulation of plasma membrane NHE
activity in rat vascular smooth muscle cells.18 Therefore,
we tested whether p38 could also be involved in
1A-AR–mediated regulation of sarcolemmal NHE
activity in adult rat ventricular myocytes. However, as
illustrated in Figure 6, neither
phenylephrine nor A61603 produced a significant increase in
p38 activity. In contrast, osmotic stress, induced by exposure to 0.5
mol/L sorbitol and used as a positive control, produced a significant
increase in p38 activity (Figure 6). The common inability of the
1-AR agonists to increase p38 activity at
concentrations that were sufficient to increase sarcolemmal NHE
activity precludes a role for the p38 pathway in
1A-AR–mediated regulation of the
exchanger.
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Downstream Effectors of ERK1/2
The 90-kDa ribosomal S6 kinase (p90rsk),
which is activated by ERK1/2, has been shown to
phosphorylate the regulatory domain of
NHE-117 27 28 and may mediate serum- or endothelin-induced
stimulation of NHE activity in cultured fibroblasts27 and
neonatal rat ventricular myocytes.28 To
determine whether p90rsk could be a downstream
effector in ERK-mediated regulation of the sarcolemmal NHE in adult rat
ventricular myocytes, we determined the effects of
1-AR stimulation on the activity of this
kinase. As shown in Figure 7, both
phenylephrine and A61603 significantly increased
p90rsk activity. The activation of
p90rsk by 1-AR
stimulation was abolished by PD98059 but unaffected by GF109203X,
suggesting that such activation occurred via an ERK-dependent but
PKC-independent pathway. This is consistent with an effector
role for p90rsk in ERK-mediated regulation of the
sarcolemmal NHE, in response to 1A-AR
stimulation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our main novel findings, which were obtained in adult rat ventricular myocytes, are that (1) inhibition of either MEK (the upstream activator of ERK1/2) or PKC abolishes stimulation of sarcolemmal NHE activity by the
1-AR agonists phenylephrine and
A61603; (2) inhibition of MEK, but not PKC, abolishes ERK activation by
both agonists; (3) activity of p90rsk, a putative
NHE-1 kinase, is regulated in parallel with that of ERK1/2; and (4)
phenylephrine and A61603 do not activate p38.
The ability of the MEK inhibitor PD98059 to abolish
phenylephrine- and A61603-induced increases in the
activities of both sarcolemmal NHE and cellular ERK1/2 provides the
first evidence that ERK activation is a critical step in
1A-AR–mediated stimulation of the exchanger
in adult rat ventricular myocytes. This finding, considered
together with our recent work in the same system on the regulation of
sarcolemmal NHE activity via the angiotensin II type
1 (AT1) receptor6 and other
pertinent data from noncardiac cells15 16 17 and cultured
neonatal rat ventricular myocytes,28 29
suggests that the ERK pathway is a critical regulator of NHE-1 activity
in response to multiple stimuli in various cell types. Furthermore, the
parallel changes observed in NHE, ERK1/2, and
p90rsk activities in response to
1-AR stimulation, in the absence or presence
of the MEK and PKC inhibitors, are consistent with
an effector role for p90rsk in ERK-mediated
regulation of the sarcolemmal NHE. In this regard, recent studies have
revealed that the regulatory domain of NHE-1 is a substrate for
p90rsk17 27 28 and that
phosphorylation of NHE-1 by p90rsk at
Ser703 stimulates exchanger activity.27
Our finding that PKC inhibition by GF109203X also abolishes
1A-AR–mediated stimulation of sarcolemmal NHE
activity supports earlier data from Wallert and
Fröhlich,3 who studied the effects on exchanger
activity of the 1-AR agonist
6-fluoronorepinephrine, and from studies with other
GqPCR agonists, such as endothelin,4
thrombin,5 and angiotensin II.6
In another pertinent study,14 however, GF109203X was shown
not to inhibit phenylephrine-induced stimulation of
sarcolemmal NHE activity. In that study,14
phenylephrine was used at a concentration of 100
µmol/L, which is 10-fold greater than that used in our present
work. Furthermore, this concentration is 
80-fold greater than the
EC50 value of phenylephrine for
stimulation of sarcolemmal NHE activity13 or
phosphoinositide hydrolysis30 in adult rat
ventricular myocytes and for translocation of PKC
in
neonatal rat ventricular myocytes.20 To
determine whether the difference in agonist concentration could account
for the contrasting effects of GF109203X in our study and that by
Pucéat et al,14 we carried out additional
experiments with a 10-fold greater concentration (100 µmol/L) of
phenylephrine. In these experiments, GF109203X failed to
inhibit the stimulation of sarcolemmal NHE activity by
phenylephrine, which increased
JH6.9 from 4.1±0.5 to 9.5±0.8
mmol · L-1 ·
min-1 (P<0.05) when administered
alone and from 3.5±0.6 to 8.4±1.2 mmol ·
L-1 · min-1
(P<0.05) when administered after pretreatment with
GF109203X (8 cells per group, from 3 hearts). This suggests that in the
presence of a supramaximal 1-AR agonist
concentration, non–PKC-mediated pathways may be sufficient to effect
increased sarcolemmal NHE activity. However, with agonist
concentrations that are likely to be of greater
physiological relevance, PKC activation appears to
be a necessary component of the pertinent signaling pathways distal to
the 1A-AR.
The common ability of GF109203X and PD98059 to inhibit
1A-AR–mediated stimulation of sarcolemmal NHE
activity may suggest that PKC and ERK are proximal and distal
components, respectively, of a contiguous NHE-regulatory signaling
pathway. Indeed, our recent work in an identical system has shown that
PKC and ERK1/2 participate in such a contiguous pathway in response to
AT1 receptor stimulation.6 In our
present work, however, ERK activation by the
1-AR agonists was not prevented by GF109203X
(Figure 4). This indicates that PKC and ERK1/2 mediate largely
independent signaling pathways and that the activation of both pathways
is necessary to achieve 1A-AR–mediated
stimulation of sarcolemmal NHE activity. With regard to the inability
of GF109203X to prevent ERK activation by
1-adrenergic stimulation, it is notable that
1A-AR–mediated ERK activation has recently
been reported to be PKC independent in PC12 cells stably transfected
with this receptor subtype.31 Furthermore, at a
concentration of 1 µmol/L, GF109203X has been shown to produce
only marginal inhibition of endothelin-induced ERK activation in
neonatal rat ventricular myocytes.21 This
observation is similar to our present findings in adult rat
ventricular myocytes, in which the same concentration of
GF109203X reduced the magnitude but did not prevent the occurrence of
significant ERK activation by 1-adrenergic
stimulation (Figure 4). We did not test higher concentrations of
GF109203X because 1 µmol/L was sufficient to abolish PMA-induced
ERK activation (which confirms that it was sufficient to inhibit
PKC-mediated responses) and due to concern for potential nonspecific
effects.26
Significant ERK activation was achieved through the exposure of adult
rat ventricular myocytes to PMA (Figure 5), which
illustrates that PKC can function as a proximal activator
of the ERK pathway in this cell type. However, our observation that
GF109203X prevented ERK activation by PMA (Figure 5) but not
that by phenylephrine or A61603 (Figure 4) indicates
that the PKC-mediated mechanism is not the major mechanism of ERK
activation in response to 1-adrenergic
stimulation. This contrasts with our recent findings regarding ERK
activation via the AT1 receptor6 and
suggests the existence of receptor-specific differences in the role of
PKC in GqPCR-mediated ERK activation.
In contrast to recent reports in neonatal rat ventricular
myocytes21 and intact adult rat hearts,19 we
found no activation of p38 in response to either
1-AR agonist. This points toward a difference
between neonatal and adult myocyte preparations in
GqPCR-mediated regulation of p38 activity,
although it is unclear whether this reflects a maturational
difference or arises from the maintenance of neonatal
cells in culture. It should also be noted that in the earlier studies,
neonatal myocytes21 or isolated hearts19 were
exposed to 100 µmol/L phenylephrine, which produced
peak p38 activation after 10 minutes19 21 In contrast, in
our study, myocytes were exposed to 10 µmol/L
phenylephrine for 3 minutes (which was sufficient to
stimulate the sarcolemmal NHE) before the assessment of p38 activity.
These differences in agonist concentration and duration of exposure may
contribute to the distinct findings. Regardless of these issues, the
inability of phenylephrine and A61603 to alter p38 activity
in the present study precludes a role for the p38 pathway in
NHE-regulatory signaling mechanisms distal to the
1A-AR in adult rat ventricular
myocytes.
Our results have shown that in isolated adult rat
ventricular myocytes,
1A-AR–mediated stimulation of sarcolemmal NHE
activity requires activation of the ERK (but not the p38) pathway of
the MAPK cascade. Activation of PKC is also required for this response,
but PKC and ERK are independent regulators of NHE activity in response
to 1A-AR stimulation. Stimulation of NHE
activity by the ERK pathway is likely to occur via activation of
p90rsk, which phosphorylates the
exchanger at Ser703 and may alter its interaction with accessory
proteins that regulate exchanger activity.27 Although the
mechanism through which PKC contributes to
1A-AR–mediated stimulation of NHE activity is
unknown, PKC does not directly phosphorylate the regulatory
domain of the exchanger,32 and altered
phosphorylation of accessory proteins may play an
important role. In view of the potential
physiological and
pathophysiological significance of
1-adrenergic stimulation of sarcolemmal NHE
activity, further work is required to fully characterize the relevant
signaling pathways.
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Acknowledgments |
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This work was supported in part by grants from the Dunhill Medical Trust and the Special Trustees of Guy’s Hospital. Dr Avkiran holds a Senior Lectureship Award (BS/93002) from the British Heart Foundation.
Received September 14, 1999; accepted November 10, 1999.
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