Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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ABSTRACT |
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Previously, we reported that cell-cell contact regulates K+ channel mRNA expression in cultured adult rat cardiac myocytes. Here we show that exposing cardiac myocytes to tyrosine kinase inhibitors (genistein, tyrphostin A25), but not inactive analogs, prevents downregulation of Kv1.5 mRNA and upregulation of Kv4.2 mRNA normally observed when they are cultured under low-density conditions. Furthermore, cardiac myocytes cocultured with cells that endogenously (Mv 1 Lu) or heterologously (Chinese hamster ovary cells) express the receptor-type protein tyrosine phosphatase µ (RPTPµ) display Kv1.5 mRNA levels paralleling that which was observed in myocytes cultured under high-density conditions and in intact tissue. In contrast, myocytes cocultured with control cells failed to produce this response. Finally, it is shown that Kv4.2 mRNA expression is unaffected by RPTPµ. These findings reveal that multiple tyrosine phosphorylation-dependent mechanisms control cardiac myocyte K+ channel genes. Furthermore, we conclude that RPTPµ specifically regulates cardiac myocyte Kv1.5 mRNA expression. Thus this receptor protein tyrosine phosphatase may be important in responses to pathological conditions associated with the loss of cell-cell interactions in the heart.
receptor-type protein tyrosine phosphatase µ; cell-cell contact; rat ventricular myocyte; voltage-gated potassium channel; gene expression
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INTRODUCTION |
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RECENTLY WE REPORTED that voltage-gated K+ channel gene expression in cardiac myocytes is influenced by signaling induced by cell-cell contact (14). This could be important for the heart because cellular excitability can be modified by regulating the expression of these channel subunits (17, 27, 28). In fact, reduced cell-cell contact has been identified in the necrotic/adjacent regions following ischemic heart disease (19, 23, 32), a pathology frequently leading to altered cardiac physiology. Consequently, identifying the pathway by which cell-cell contact regulates cardiac K+ channel gene expression may lead to novel therapeutic approaches to the management of such diseases as myocardial infarction.
Tyrosine phosphorylation of proteins, controlled by the reciprocal actions of tyrosine kinases and phosphatases, represents an important mechanism for many physiological processes, including cell contact. Once thought to be a secondary player, protein tyrosine phosphatases (PTPs) have received growing attention for their role in these processes. The receptor-type protein tyrosine phosphatase µ (RPTPµ) is an appealing candidate for mRNA regulation in myocytes by cell-cell contact. This membrane spanning phosphatase is expressed in the heart (11) and interacts in a homophilic fashion via its extracellular domain (1, 4, 13). Although no physiological function has yet been assigned to this phophatase, this characteristic has led to the proposal that RPTPµ may contribute to cell-cell adhesion. This is supported by evidence that RPTPµ interacts with the cadherin/catenin system (2, 3). Furthermore, the surface expression of RPTPµ is regulated by cell-cell contact (12). Whereas the impact of this response on cellular function is not known, it is known from work on other PTPs that changes in tyrosine phosphatase activity parallel changes in expression (10, 21, 25). Therefore, we set out to investigate the role played by RPTPµ and protein tyrosine phosphorylation in cell-cell contact mediated K+ channel mRNA regulation in cardiac myocytes.
Here we present evidence that suggests cell contact reduces tyrosine phosphorylation to regulate the expression of cardiac K+ channel genes. Furthermore, despite some commonality, different cell contact signaling pathways are utilized by cardiac myocytes to regulate the expression of the Kv1.5 and Kv4.2 genes. Finally, we reveal for the first time that RPTPµ can regulate cardiac myocyte Kv1.5 gene expression through cell-cell interactions.
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MATERIALS AND METHODS |
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Chemicals. The tyrosine kinase inhibitors and their inactive analogs were purchased from LC Laboratories (tyrphostins A25, A1) or Calbiochem (genistein, daidzein) and diluted in DMSO. All other chemicals and drugs used in this study were obtained from Sigma Chemical except where noted otherwise. Media were purchased from Life Technologies or Sigma.
Cell lines. Mv 1 Lu (American Type Tissue Collection; ATCC) and Chinese hamster ovary (CHO)-K1 cells (ATCC) were cultured with DMEM containing 10% fetal bovine serum (FBS) or F-12 medium containing 10% FBS, respectively. Both cell lines were maintained at 37°C in a 5% CO2-humidified air incubator. CHO cells were transfected with either pMT2m, an expression vector encoding a full length mouse RPTPµ (kindly provided by Drs. Zondag and Moolenaar, Netherlands Cancer Institute) (11) or pEGFP-C1 (Clontech) using Lipofectamine reagent (Life Technologies) according to the directions supplied by the manufacturer.
Isolation of ventricular myocytes. Female Sprague-Dawley rats (195-225 g) were obtained from Hilltop Lab Animals. For all experiments shown, rats were injected intraperitoneally with 50 mg/kg dexamethasone in sesame oil to increase Kv1.5 gene expression (30). However, it was previously demonstrated that changes in cell-cell contact led to quantitatively similar changes in Kv1.5 or Kv4.2 mRNA expression in ventricular myocytes isolated from naive animals and from dexamethasone-injected rats (4). Therefore, it seems unlikely that this treatment had any impact on the effects described in this report.
The protocol used for the acute dissociation of cardiac myocytes from whole ventricles has been described previously (14, 18). Briefly, animals were anesthetized with Metofane (methoxyflurane; Pitman-Moore), the hearts excised, and placed in ice-cold solution 1 [final concentrations (in mM) 5.4 KCl, 0.82 MgSO4, 120 NaCl, 1.0 NaH2PO4, 1.7 MgCl2, 2.0 L-glutamine, 4.4 NaHCO3, 21.2 HEPES, 1.5 KH2PO4, 8.0 NaOH, 11.6 glucose, 1× essential vitamins, and 1× essential amino acids]. After trimming off fat and lung tissue, the ascending aorta was cannulated and the heart hung from a Langendorff perfusion apparatus. The perfusion was conducted in a 37°C warm room. The heart was perfused first with solution 2 (solution 1 supplemented with 0.1 µmol/L insulin and an additional 5.0 mM MgCl2 and 1.0 mM NaOH) followed by perfusion with solution 3 [solution 2 supplemented with 0.06% collagenase (type II; Worthington Biochemical)] and an additional 0.01 mM CaCl2. The two solutions used to perfuse the heart were continuously bubbled with 95% O2-5% CO2 for the entire perfusion period. Approximately 16 min after beginning perfusion with the collagenase containing solution, the lower three-fourths of the heart, containing right and left ventricular tissue, was removed and returned to room temperature where it was placed into a 60-mm culture dish containing 10 ml high K+ solution [final concentrations (in mM) 40 KCl, 70 KOH, 20 KH2PO4, 20 taurine, 50 monopotassium glutamate, 10 HEPES, 0.5 EGTA, 3.0 MgCl2, and 1 mg/ml BSA]. The ventricular tissue was then cut into small pieces, triturated with a fire-polished Pasteur pipette, and poured over a 200-µm nylon mesh into a 15-ml centrifuge tube. Cells were washed twice with solution C (solution 1 supplemented with 5 mg/ml BSA, 1.25 mg/ml taurine, 5.0 mM MgCl2, 1.0 mM NaOH, and 0.01 mM CaCl2). This procedure yields ~9 × 106 ventricular myocytes. Cardiac myocytes were cultured at 37°C in a 5% CO2-humidified air incubator in medium 199 containing 25 mM HEPES and in the absence of L-glutamine. Unless noted otherwise, the yield of cells from a single heart was divided equally into three cultures. See figure legends for further details. For coculture experiments with adult cardiac myocytes, Mv 1 Lu and CHO cells were dislodged by scraping after a 15-min exposure to Hanks' balanced salt solution containing 2 mM EDTA. Cells were then resuspended in the same medium used for culturing cardiac myocytes. Approximately 107 Mv 1 Lu or CHO cells were employed in each coculture dish.mRNA measurements.
Total RNA was isolated according to the procedure of Chomczynski and
Sacchi (5). mRNA abundance was determined by RNase protection assays (14, 18, 27, 30, 31). RNA probes were synthesized
from Xba I-linearized pGEMA-Kv1.5 plasmid DNA (26, 30),
EcoR I-linearized Kv4.2 plasmid DNA (31), or Hind
III-linearized cyclophilin plasmid DNA (6, 30) using
[-32P]UTP and the appropriate polymerases.
Total RNA (10 µg) was hybridized with one of the K+
channel and cyclophilin RNA probes overnight at 50°C in 40-mM PIPES-NaOH (pH 6.4), 1 mM EDTA, 0.4 mol/L NaCl, 80% formamide. RNase
digestion and recovery of the protected fragments was accomplished as
described previously (14, 18, 27, 30, 31). Samples were subsequently
fractionated through 4% denaturing acrylamide gels. The gels were
allowed to air-dry and were used to expose a PhosphorImager cassette
(Molecular Dynamics). The intensity of K+ channel and
cyclophilin mRNA signals were determined with a Molecular Dynamics
PhosphorImager. The background subtracted K+ channel mRNA
signals were normalized to the signals of the internal control mRNAs.
Normalized signals from experimental groups were expressed as a
percentage of the signal obtained in the control. All error bars are
SE. Student's t-test was performed to determine the level of
significance. Values were considered significantly different when
P
0.05.
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RESULTS |
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A rapid and dramatic downregulation of Kv1.5 mRNA expression occurs
when cardiac myocytes are cultured under low density (4). Exposing
these cultures to tyrosine kinase inhibitors prevented this phenomenon.
We conducted a number of experiments in which cardiac myocytes were
exposed to genistein (0.3 or 0.5 mM), daidzein (0.3 or 0.5 mM), or
vehicle (Fig. 1, A and
B). Figure 1A shows a representative
RNase protection assay of an experiment in which low-density cultures
of cardiac myocytes were exposed to 0.3 mM genistein or 0.3 mM
daidzein. As can be seen in this figure, Kv1.5 mRNA expression in
myocytes exposed to genistein greatly exceeds that which is observed in
control cells. Quantitation of these experiments demonstrated that
there was no significant concentration-dependent effect for either drug
within this range. However, Kv1.5 mRNA expression in myocytes exposed
to genistein was significantly elevated over vehicle-exposed cells
(509.7 ± 154.3%; n = 7). Exposing cardiac myocyte cultures
to another tyrosine kinase inhibitor, tyrphostin A25, produced a
similar effect on Kv1.5 mRNA expression (Fig. 1C). The effects
of genistein and tyrphostin A25 appear to be due to tyrosine kinase
inhibition because equivalent concentrations of the inactive analogs
did not have similar effects. For example, Kv1.5 mRNA expression in
myocytes exposed to daidzein was 140.6 ± 22.1 (n = 7) of vehicle-exposed controls (Fig. 1B). Like
daidzein, the negative control, tyrphostin A1 also failed to produce
any significant effect on Kv1.5 mRNA expression (Fig. 1C).
Moreover, in one exploratory experiment, the nonspecific
serine/threonine kinase inhibitor H7 also had no effect (data not
shown). It should also be pointed out that inhibiting tyrosine kinase
activity in low-density cultures produces a 2.3-fold greater effect on
Kv1.5 mRNA expression than in high-density cultures (data not shown). Thus these results are consistent with the proposal that cell-cell contact reduces tyrosine phosphorylation to regulate the expression of
cardiac Kv1.5 mRNA.
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The reduction in tyrosine phosphorylation produced pharmacologically
could mimic the effect of endogenous membrane spanning tyrosine
phophatases. RPTPµ seemed to be a candidate for regulation of
K+ channel mRNA by cell-cell contact due to its tyrosine
phosphatase activity, regulation by cell density, and its expression in
the heart (11, 12). To explore this possibility, we first employed Mv 1 Lu cells in coculture experiments. These epithelial cells derived from
the lung are known to express RPTPµ (11). However, because these
cells are derived from mink, their mRNA does not interfere with RNase
protection assays of rat Kv1.5 mRNA (data not shown). Kv1.5 mRNA
expression in myocytes cocultured with Mv 1 Lu cells was found to be
83.7 ± 29.5% (n = 3) of that which was observed in
high-density myocyte cultures (Fig.
2A). This was almost four times
that which was observed in myocytes cultured under low density alone.
This effect was not due to a modification of myocyte-myocyte
interactions because myocytes cocultured with a similar number of CHO
cells expressed Kv1.5 mRNA levels that paralleled those seen in
low-density myocyte cultures (n = 4). Because the magnitude of
the effect of Mv 1 Lu cells varied, these results were not
statistically significant. However, Mv 1 Lu cells always increased the
Kv1.5 signal compared with controls in each experiment. More
importantly, the possible regulation of cardiac Kv1.5 mRNA by one cell
line over another could have been mediated by any number of cell
surface molecules. Therefore, we did not seek to further reproduce this
result. Yet, the trend in the Mv 1 Lu data coupled with the results
with tyrosine kinase inhibitors stimulated us to more rigorously
explore whether RPTPµ plays a stimulatory role in cell contact
regulation of Kv1.5 K+ channel mRNA expression.
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Therefore, we transfected CHO cells with a vector containing a full-length mouse RPTPµ cDNA (11). Control experiments showed that CHO cells transfected with an EGFP expression vector, like untransfected CHO cells, did not significantly affect Kv1.5 gene expression in cocultured cardiac myocytes. However, cardiac myocyte Kv1.5 mRNA expression in the presence of exogenous RPTPµ was much higher (Fig 2C). Thus RPTPµ regulates cardiac myocyte Kv1.5 mRNA expression though cell-cell interactions.
Modulation of protein tyrosine phosphorylation in cultured cardiac
myocytes also led to changes in Kv4.2 mRNA expression. Myocytes exposed
to genistein express significantly less Kv4.2 mRNA than vehicle-exposed
myocytes (Fig 3A). However, Kv4.2
mRNA abundance in myocytes from cultures exposed to daidzein were not different from those exposed to vehicle. This same trend was also observed when myocytes were exposed to tyrphostin A25, whereas the
inactive analog, tyrphostin A1, had no effect on Kv4.2 mRNA abundance
(Fig. 3B). Furthermore, like Kv1.5, inhibiting tyrosine kinase
activity has a greater effect on Kv4.2 mRNA expression in low-density
than high-density myocyte cultures (data not shown). Thus these results
suggest that protein tyrosine phosphorylation also participates in
cell-cell contact-dependent regulation of cardiac myocyte Kv4.2 mRNA
expression.
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Whereas the results from experiments using tyrosine kinase inhibitors highlight the similarity between Kv1.5 and Kv4.2 mRNA regulation by cell-cell contact, previous work by our laboratory which examined the reversibility of this phenomenon (14) suggests that these two K+ channel genes are not regulated by an identical mechanism. To further explore this observation, we also tested whether RPTPµ regulates Kv4.2 mRNA expression. Again, cardiac myocytes were cocultured with CHO cells transfected with an expression vector encoding the full-length mouse RPTPµ. However, unlike with Kv1.5, this manipulation had no impact on cardiac myocyte Kv4.2 mRNA levels (Fig. 3C). As expected, GFP-transfected CHO cells produced no changes in Kv4.2 mRNA expression in coculture experiments. Thus despite some commonality, different cell contact signaling pathways are utilized by cardiac myocytes to regulate the expression of Kv1.5 and Kv4.2 genes.
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DISCUSSION |
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Protein tyrosine phosphorylation regulates cardiac K+ channel mRNA expression. Previously, we found that culturing adult cardiac myocytes under low density produces rapid and dramatic changes in Kv1.5 and Kv4.2 mRNA expression (14). This report provides evidence that tyrosine phosphorylation is likely to participate in the mechanism by which cell-cell contact reciprocally regulates these cardiac K+ channel genes. Specifically, we found that inhibiting tyrosine kinase activity prevents the downregulation of Kv1.5 mRNA and the upregulation of Kv4.2 produced by low cell density. In principle, these effects could have been due to the inhibition of other kinases because somewhat high concentrations of genistein and tyrphostin A25 were required. However, results with the nonspecific serine/threonine kinase inhibitor H7, and inactive analogs such as daidzein and tyrphostin A1 rule against this possibility. Interestingly, H7 potently regulates Kv1.5 gene expression in pituitary cells (29). Thus it appears that the phosphorylation mechanisms that regulate this gene are cell type specific. Most importantly, the tyrosine kinase inhibitor data are consistent with the hypothesis that direct contact between myocytes decreases protein tyrosine phosphorylation to regulate Kv1.5 and Kv4.2 K+ channel mRNA expression. A previous study has established that tyrosine phosphorylation acutely and directly regulates Kv1.5 K+ channel gating activity (15). Similarly, a role for cell-cell interactions in the control of neuronal K+ channel activity has been documented (7, 33). However, this report establishes for the first time that tyrosine phosphorylation plays an important role in regulating Kv channel mRNA expression.
RPTPµ regulates cardiac Kv1.5 K+ channel mRNA expression via cell-cell contact. RPTPs are appealing candidates for K+ channel gene regulation by cell contact and tyrosine phosphorylation, as their activity and expression are known to be regulated by cell-cell contact (9, 10, 21, 24, 25). We investigated the possibility that RPTPµ contributes to regulation of cardiac Kv mRNAs because it is expressed in the heart (11) and because its surface expression has been shown to be regulated by changes in cell-cell contact (12). We found that coculturing myocytes with Mv 1 Lu cells, a cell line known to express RPTPµ (11), led to Kv1.5 mRNA levels in the myocytes that approximated the high-density situation. In theory, this effect could be due to any number of Mv 1 Lu cell surface molecules. However, Kv1.5 mRNA expression was also increased in myocytes cocultured with CHO cells transfected with a full-length mouse RPTPµ cDNA. It seems likely that this effect results from the surface expression of RPTPµ molecules because both untransfected CHO cells and CHO cells transfected with a GFP cDNA failed to produce this response in myocytes. Therefore, these findings reveal for the first time that RPTPµ can regulate channel gene expression through cell-cell interactions. Indeed, to our knowledge, this is the first report of a role for any RPTP in control of any mammalian gene. Furthermore, it is the first documented function for RPTPµ in the heart.
The surface molecule response for cell contact-dependent regulation of Kv4.2 mRNA also survives paraformaldehyde fixation (14). However, evidence suggested different pathways were involved. For example, regulation of Kv1.5 mRNA by cell contact is irreversible whereas Kv4.2 mRNA expression can be readily reversed by continually altering the culture density. The observation that RPTPµ transfected CHO cells had no impact on cardiac myocyte Kv4.2 mRNA expression in coculture experiments supports this conclusion. Thus despite some commonality, different cell contact signaling pathways, initiated by different cell surface molecules, are utilized by cardiac myocytes to regulate the expression of Kv1.5 and Kv4.2 genes. Clearly, RPTPµ acts specifically to regulate Kv1.5 mRNA expression.Possible mechanisms and importance of cell contact-dependent control of Kv1.5 gene expression. Because downregulation of Kv1.5 mRNA abundance in low-density myocyte cultures is irreversible (14), it seems likely that culturing myocytes under these conditions promotes a long-term loss of phosphatase activity, perhaps, through loss in protein abundance. In fact, RPTPµ has been shown to be rapidly cleared from the cell surface when transfected Swiss 3T3 cells are cultured under low-density settings (12). Furthermore, research on other PTPs has demonstrated that changes in protein abundance are paralleled by changes in phosphatase activity (10, 21, 25). Thus we propose that culturing cardiac myocytes under low cell-cell contact settings promotes the downregulation of RPTPµ protein. This, in turn, must lead to increased tyrosine phosphorylation that ultimately decreases Kv1.5 mRNA abundance.
Many changes in Kv1.5 mRNA arise from alteration of transcriptional activity (16, 27, 28, 29). If changes in cell-cell contact regulate K+ channel mRNA expression via regulated transcription activity, then NF-Conclusions. This report demonstrates that it is likely that tyrosine phosphorylation plays an important role in long-term control of cardiac excitability. Furthermore, our results suggest that RPTPµ is a transducer of cell-cell contact-dependent signaling between cardiac myocytes. Because specific inhibitors of this phosphatase are not available, the function of RPTPµ in the intact heart has not been investigated. Yet, future studies may reveal that RPTPµ is important in responses to pathological conditions associated with the loss of cell-cell interactions in the heart.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-55312 and by an American Heart Association (Pennsylvania Affiliate) Grant-in-Aid. K. M. Hershman was supported by individual NHLBI Postdoctoral Fellowship Grant HL-09347.
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FOOTNOTES |
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E. S. Levitan is an Established Investigator of the American Heart Association.
Present address of K. M. Hershman: Pulmonary Allergy and Critical care Medicine, Univ. of Pittsburgh, 449 Scaife Hall-3550 Terrace St., Pittsburgh, PA 15261.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. S. Levitan, Dept. of Pharmacology, Univ. of Pittsburgh, E1351 Biomedical Science Tower, Pittsburgh, PA 15261 (E-mail: levitan{at}server.pharm.pitt.edu).
Received 15 July 1999; accepted in final form 17 September 1999.
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