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-adrenergic
receptor downregulation in rat skeletal muscle
1 Département de Kinésiologie; 2 Groupe de Recherche sur le Système Nerveux Autonome; 3 Département de Physiologie et Institut de Cardiologie de Montréal; 4 Centre de Recherche de l'Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Québec, Canada H3C 3J7
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Farnesylation represents an essential
posttranslational modification of several well-defined proteins
implicated in the homologous desensitization of the 
-adrenergic
receptor (-ADR). The following study examined the effect of a novel
farnesyltransferase inhibitor, BMS-191563, on agonist-mediated -ADR
downregulation in skeletal muscle. Female Sprague-Dawley rats were
treated for 12 days with the 2-adrenergic agonist
clenbuterol (4 mg/kg) with or without the concurrent administration of
BMS-191563 (2 mg · kg
1 · day1).
Clenbuterol promoted gastrocnemius muscle hypertrophy, whereas the
soleus muscle was unaffected. Total -ADR density was decreased by 45 and 40% in the soleus and medial gastrocnemius (MG), respectively, after clenbuterol treatment. BMS-191563 treatment did not prevent clenbuterol-stimulated MG hypertrophy, but markedly attenuated -ADR
downregulation in both muscle types. This latter effect in the soleus
muscle was not associated with the inhibition of Ras
farnesylation. Likewise, in rat cardiac fibroblasts,
isoproterenol-mediated decrease of total -ADR density was abrogated
by the prior treatment with BMS-191563. Collectively, these data
demonstrate that the mechanism(s) implicated in agonist-mediated
-ADR downregulation was sensitive to BMS-191563, thereby suggesting
the involvement of farnesylated proteins.
sympathetic system; cardiac fibroblasts; homologous desensitization; clenbuterol; farnesylation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HOMOLOGOUS
DESENSITIZATION of the -adrenergic receptor (-ADR)
represents an adaptive response commonly observed in various disease
states associated with a hyperactivity of the sympathetic system
(30). The uncoupling of the -ADR from its
heterotrimeric G protein characterizes the initial event of
desensitization after acute exposure to agonist (11). This
process involves the phosphorylation of the -ADR by a unique family
of G protein-coupled receptor kinases (GRK) and leads to the subsequent
binding of the protein -arrestin (33). The
-ADR/-arrestin complex is sequestered in endosomes, whereupon the
receptor can then be recycled to the membrane after removal of the
agonist (11, 33). However, the prolonged agonist exposure
(>1 h) will result in the translocation of the -ADR to lysosomes
and targeting for degradation (19). This latter process of
homologous desensitization is referred to as receptor downregulation
(19). Although the mechanism(s) implicated in receptor
downregulation remains to be completely resolved, several studies have
suggested receptor sequestration may represent a prerequisite event
(2, 13).
The posttranslational addition of isoprenoid lipids via a process
termed prenylation represents a prerequisite event of numerous proteins
to achieve proper cellular localization and full biological activity
(18). The cytosolic enzyme farnesyltransferase attaches a
15-carbon farnesyl isoprenoid to the cysteine residue of the CAAX (C,
cysteine; A, aliphatic amino acid; X, either serine, methionine,
glutamine, or alanine) motif (10). The addition of the
farnesyl group leads to the proteolytic cleavage of the remaining three
COOH-terminal amino acids and subsequent methylation of the prenylated
cysteine. A second cytosolic prenyltransferase termed
geranylgeranyltransferase has been identified and attaches a
20-carbon geranylgeranyl isoprenoid to the cysteine residue of
the CAAX motif, if the X amino acid is a leucine residue
(8). Interestingly, the GRK1 isoform of the GRK family
contains a CAAX motif, whereas GRK2 and GRK3 are not prenylated but
display two protein motifs implicated in the targeting of these
proteins to the plasma membrane: a G
-binding domain and a
pleckstrin homology domain (6, 8, 26). Analogous to GRK1,
the attachment of the G-subunit to the plasma membrane requires
the posttranslational prenylation of the -subunit. The G1-,
8-, and 11-isoforms are targets of farnesyltransferase, whereas
the remaining G-isoforms are geranylgeranylated (27).
On the basis of these observations, the selective inhibition of
prenylation may represent a mechanism modulating -ADR
desensitization and/or downregulation after the chronic
exposure to agonist. In this regard, the following study used a
pharmacological approach to better understand the relationship between
farnesylation and agonist-mediated -ADR downregulation in skeletal muscle.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Protocol
Experiments were conducted in accordance with the guidelines of the Canadian Council for the Protection of Animals and approved by the Ethics and Research Committee of the University of Montreal. Thirty-two female Sprague-Dawley rats (Charles River, St-Constant, Canada) with an initial weight of 150-175 g were used. Rats were housed individually at a constant temperature of 21°C and had free access to water and food. After a 2-day acclimatization period, the animals were randomly separated into four experimental groups: control, BMS-191563 (peptidomimetic farnesyltransferase inhibitor; Bristol-Myers Squibb, Princeton, NJ), clenbuterol (selective2-adrenergic agonist; Sigma, St. Louis, MO), and BMS-191563 and clenbuterol. BMS-191563 (2 mg · kg1 · day1) was
injected intraperitoneally for 14 days, whereas control animals
received an injection of the equivalent volume of saline 0.9%.
Clenbuterol was mixed into a powdered form of standard laboratory rat
diet (ProLab RMH 4018, Syracuse, NY) at a concentration of 4 mg/kg of
food and administered for 12 days (22). In the BMS-19563 plus clenbuterol-treated rats, clenbuterol was added to the diet 2 days
after the start of the BMS-191563 treatment.
Contractile Properties
At the end of the treatment period, the animals were anesthetized with pentobarbital sodium (45 mg/kg; Maple Leaf, Cambridge, Canada) for the measurement of in situ contractile properties of the medial gastrocnemius (MG) muscle, as previously described (23). Contractile properties were recorded on computer or FM tape, and, after the experiment was completed, the soleus and gastrocnemius muscles were excised, weighed, frozen in liquid nitrogen, and stored at
80°C.
Cultured Neonatal Rat Cardiac Fibroblasts
Cardiac fibroblasts were isolated from 1- to 3-day-old Sprague-Dawley rat pups (Charles River), as previously described (5). Experiments were performed on second passage cells that were plated at a density of 100-200 cells/mm2 for a period of 24-36 h in DMEM containing 7% FBS. Cells were subsequently washed and the media was changed to serum-free DMEM containing insulin 5 µg/ml and sodium selenite 5 ng/ml (Collaborative Biomedical, Bedford, MA) for 48 h before the experimental protocol.Measurement of Total -ADR Density
80°C) skeletal muscle tissue was prepared
as previously described (23). For cardiac fibroblasts, 250 µl of lysis buffer (75 mM Tris, 12.5 mM MgCl2, 2 mM EDTA,
1 µg/ml leupeptin, 1 µg/ml aprotinin, and 100 µM PMSF) was added
to each plate and cells were scraped and homogenized with a 23-gauge
needle. The skeletal muscle plasma membrane pellet and the total
cardiac fibroblast lysate were used immediately for analysis. Protein content was measured with the Bradford method using bovine serum albumin as a standard.
-ADR density was measured in triplicate using saturating
concentrations of [125I]iodocyanopindolol (New England
Nuclear, Mandel, Guelph, Canada) with or without 10 µM alprenolol
(Sigma), as previously described (23). Radioactivity was
measured using a gamma counter (LKB 1271, PerkinElmer Life Sciences,
Turku, Finland). Specific binding was calculated as the difference
between total binding and nonspecific binding. -ADR density is
expressed in femtomoles per milligram of protein. In cardiac
fibroblasts, -ADR density was found to be 57 ± 9 fmol/mg
protein (n = 4).
Western Blot Analysis of Ras and Extracellular-Signal Regulated Kinase
Distribution. The cytosolic and particulate fractions of total soleus muscle lysate were prepared as previously described (4). One hundred micrograms of particulate and cytosolic protein was loaded on a 10% SDS-polyacrylamide gel, and subsequently transferred to a nitrocellulose membrane (Hybond; Amersham, Baie d'Urfée, Canada). The membrane was blocked in a solution of TBS (Tris-buffered saline) 1×, 0.1% Tween, and 3% powdered milk, followed by an overnight incubation at 4°C with either a pan-Ras mouse antibody (1:250; recognizes H, N, and K isoforms; Calbiochem, LaJolla, CA), or extracellular-signal regulated kinase (ERK) rabbit antibody (1:1,000; Stressgen, Victoria, BC, Canada). The membrane was washed four times for 10 min with the initial blocking solution and subsequently treated for 1-2 h with either an anti-rabbit and anti-mouse horseradish peroxidase- conjugated secondary antibody (1:5,000; Santa Cruz Biotechnology, Santa Cruz, CA), and the immunoreactive bands were visualized using chemiluminescence (Amersham).
Immunohistochemistry Analysis of Ras in Skeletal Muscle
Frozen sections of soleus muscle from fixed Sprague-Dawley rats were cut longitudinally to 16 µm and mounted on 3-aminopropyltriethoxysilane (Sigma)-treated slides (Fisher Scientific, Ottawa, Ontario) (1). Mouse monoclonal pan-Ras antibody (recognizes H-, N-, and K-Ras; Calbiochem) was applied at a 1:100 dilution in a medium containing 1% goat serum and 25% PBS 4× and incubated for 24 h at 4°C. The slides were rinsed with a solution containing 5% goat serum, 25% PBS 4×, and 4% Triton. The second antibody, anti-mouse IgG-FITC (Santa Cruz Biotechnology), was then applied at a 1:1,000 dilution in the same medium as the first antibody and incubated for 2 h. Slides were subsequently rinsed with distilled water, dried, and mounted with glycerin. To confirm signal specificity, the second antibody was added in the absence of the primary anti-Ras antibody. In these latter experiments, an immunodetectable signal was not observed.Statistical Analysis
Data are expressed as means ± SE. Statistical significance (P < 0.05) was assessed using a two-way analysis of variance followed by a Newman-Keuls multiple-comparison test when necessary.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Body Weight, Skeletal Muscle Hypertrophy, and Contractile Function
Chronic treatment with clenbuterol increased body weight (232 ± 4 g; n = 7; P < 0.05) compared with sham treatment (218 ± 2 g; n = 7). The treatment with BMS-191563 significantly decreased body weight (207 ± 3 g; n = 9; P < 0.05) compared with sham treatment. The decrease in body weight observed with BMS-191563 was not due to a change in eating habit, as the amount of chow consumed per day in this group was similar to sham-treated animals (data not shown). No difference in body weight was observed between clenbuterol/BMS-191563 cotreated rats (232 ± 2 g; n = 9) compared with clenbuterol-treated rats. Clenbuterol administration increased gastrocnemius muscle weight from 543 ± 27 (n = 7) to 603 ± 24 (n = 7) mg muscle/100 g body wt (P < 0.05 vs. sham), which translated into an 11% hypertrophic response. By contrast, clenbuterol treatment had no growth effect in the soleus muscle (sham = 43 ± 3 vs. clenbuterol = 45 ± 3 mg muscle/100 g body wt; n = 7 for sham-treated and treated rats). As for contractile properties, a significant effect of clenbuterol was observed in the contractile and half-relaxation times (Table 1), whereas force generation (data not shown) measured in the MG muscle was unaffected. Treatment with the farnesyltransferase inhibitor BMS-191563 alone did not significantly influence skeletal muscle mass (BMS-191563 = 565 ± 21 mg muscle/100 g body wt; n = 9) or contractile function of the MG muscle (Table 1). The pretreatment of rats with BMS-191563 before the administration of clenbuterol did not alter the subsequent MG hypertrophic response (clenbuterol+BMS-191563 = 601 ± 31 mg muscle/100 g body wt; n = 9) or the associated contractile parameters (Table 1).
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BMS-191563 Modulation of -ADR Downregulation in Skeletal Muscle
-ADR density was observed with
clenbuterol treatment in both the soleus (n = 6) and
the MG muscles (n = 6) (Fig.
1). The treatment with BMS-191563 alone had no significant effect on total -ADR density (n = 6). However, clenbuterol-mediated receptor downregulation was
attenuated in the MG (n = 6) and prevented in the
soleus muscle (n = 6) by BMS-191563 pretreatment (Fig.
1).
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BMS-191563 Effect on Agonist-Mediated -ADR Downregulation in
Cultured Neonatal Rat Cardiac Fibroblasts
2-adrenergic
receptor is the predominant subtype in cultured neonatal rat cardiac
fibroblasts (20). A 24-h exposure of cardiac fibroblasts
to isoproterenol (1 µM) caused a significant decrease in total
-ADR density (n = 4 independent cardiac fibroblast
preparations) (Fig. 1). The pretreatment (4-6 h) with 50 µM
BMS-191563 had no effect on total -ADR density (n = 4). As observed in skeletal muscle, BMS-191563 treatment inhibited
isoproterenol-mediated -ADR downregulation (n = 4)
(Fig. 1).
BMS-191563 Effect on Ras Distribution in the Soleus Muscle
A putative target of farnesyltransferase is the small GTP-binding protein Ras. The function of both normal and oncogenic Ras has been shown to be absolutely dependent on the physical association to the plasma membrane (18). In the soleus muscle, immunofluorescence experiments demonstrated that immunodetectable Ras was found predominantly at the plasma membrane (Fig. 2). These data were confirmed by Western blot analysis of total soleus lysate, as immunodetectable Ras was found predominantly in the particulate fraction (Fig. 2). Overexposure revealed a very weak signal in the cytosolic fraction (data not shown). By contrast, the mitogen-activated ERK was detected predominantly in the cytosolic fraction. Overexposure revealed a weak signal in the particulate fraction, and only the p44 isoform was detected (data not shown) (Fig. 2). Despite the inhibition of clenbuterol-mediated-ADR
downregulation by the pretreatment with BMS-191563, this effect was not
associated with the redistribution of particulate Ras to the cytosolic
fraction.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Posttranslational lipid modification by cytosolic
prenyltransferases represents an essential feature of several proteins
implicated in the homologous desensitization of the -ADR
(6). The farnesylation of GRKs and/or their subsequent
recruitment to the membrane by the -dimer, of which the
-subunit is either farnesylated or geranylgeranylated, has been
implicated in the homologous desensitization of the -ADR (6,
8, 27). The farnesyltransferase inhibitor BMS-191563 has been
previously shown to inhibit the farnesylation of Ras in cardiac
myocytes (4). Moreover, the in vivo administration of
BMS-191563 (1 mg/day) in the DOCA-salt hypertensive rat ameliorated mean arterial pressure via the inhibition of Ras activity
(24). The present study demonstrated that the in vivo
treatment of female rats with BMS-191563 attenuated
2-adrenergic agonist-mediated downregulation of -ADRs
in both the soleus and MG muscles. Consistent with these results, the
treatment of cultured neonatal rat cardiac fibroblasts with BMS-191563
prevented isoproterenol-mediated -ADR downregulation. Thus these
data demonstrate the mechanism(s) implicated in agonist-mediated
downregulation of the -ADR is sensitive to BMS-191563 treatment,
thereby suggesting the potential involvement of farnesylated proteins.
As reported previously, this study demonstrated that the chronic
administration of clenbuterol promoted MG muscle hypertrophy and
altered contractile and half-relaxation times (22, 23). The action of clenbuterol in the gastrocnemius muscle occurred via
activation of 2-adrenergic receptors (17).
Although 2-adrenergic receptors have been detected in
the soleus muscle, their density may be less than that of other -ADR
subtypes, such as the 3- or the "atypical"
-adrenergic subtype (28). This disparate distribution
pattern of -ADR subtypes may in part explain the modest
nonsignificant hypertrophic response of the soleus muscle to
clenbuterol treatment compared with the MG muscle. In addition, the
different fiber makeup of the soleus (slow fibers) and MG (fast fibers)
may also contribute to the disparate hypertrophic response elicited by
clenbuterol (16). Nonetheless, the chronic administration
of clenbuterol resulted in a decrease of total -ADR density in both
muscle types. On the basis of previous studies regarding
agonist-mediated -ADR subtype regulation, the decrease in total
receptor density in both muscle types most likely reflects the
downregulation of the 2-adrenergic receptor
(3). Treatment with BMS-191563 alone had no significant
effect on total -ADR density. In addition, BMS-191563
treatment did not modify contractile indexes or the hypertrophic
response of the MG muscle after clenbuterol treatment. However, in both
muscle types, the pretreatment with BMS-191563 attenuated
clenbuterol-mediated -ADR downregulation. Analogous to the MG
muscle, the 2-adrenergic receptor represents the
predominant subtype in neonatal rat cardiac fibroblasts, whereas neither the "atypical" nor 3-adrenergic subtypes
were detected (20). Consistent with the presence of the
2-adrenergic receptor, the chronic exposure to
isoproterenol decreased total -ADR density. Moreover, as observed in
the soleus and MG muscles, the pretreatment with BMS-191563 prevented
isoproterenol-mediated -ADR downregulation in the rat cardiac
fibroblasts. Collectively, these data support the premise that
agonist-mediated -ADR downregulation may involve one or more
farnesylated proteins.
After a short time (<1 h) exposure to agonist, desensitization of the
-ADR occurs via the phosphorylation of the receptor by GRKs
(12). The GRK-mediated phosphorylation promotes the binding of the regulatory protein -arrestin, which in turn uncouples the receptor from the stimulatory G protein, Gs
(33). In addition, -arrestin binding to the
phosphorylated receptor represents a prerequisite event for the
subsequent sequestration of the receptor (13, 33). After
the long-term (>1 h) exposure to agonist, the -ADR is targeted for
degradation, a process generally referred to as downregulation
(19). In contrast to desensitization and sequestration,
the biochemical events linked to receptor downregulation remain to be
fully elucidated. At least two studies have suggested a casual link
between receptor sequestration and downregulation. Barak and colleagues
(2) demonstrated the mutation of arginine 322 of the
2-adrenergic receptor abolished both sequestration and
downregulation. In support of these latter findings, Gagnon and
colleagues (13) recently demonstrated that
-arrestin-mediated sequestration represented in part a prerequisite
event coupled to the subsequent downregulation of the
2-adrenergic receptor in HEK293 cells. It has been
established that GRK1 represents a putative target of
farnesyltransferase, whereas GRK2 and GRK3 are targeted to the plasma
membrane by the -dimer of heterotrimeric G proteins
(8). Moreover, several -subunit isoforms of the -dimer are also targets of farnesylation (27). In
this regard, farnesyltransferase inhibition may prevent the initial
prerequisite events involved in the homologous desensitization of the
-ADR. Indeed, it has been demonstrated that the biological activity of GRK1 and various -dimer combinations are exclusively dependent on prenylation (15, 21, 25). Thus these observations
provide a potential mechanism to explain in part the attenuation of
agonist-mediated -ADR downregulation in both skeletal muscle and
isolated cardiac fibroblasts by the farnesyltransferase inhibitor
BMS-191563.
The small GTP-binding protein Ras is a putative target of
farnesyltransferase, and in cultured neonatal rat cardiac myocytes, we
demonstrated the treatment with BMS-191563 resulted in a redistribution of plasma membrane-bound Ras to the cytoplasm (4, 18). To confirm the efficacy of BMS-191563 in skeletal muscle, the cellular localization of Ras was examined in the soleus muscle.
Immunofluorescence and Western blot analysis revealed Ras was
predominantly located on the plasma membrane. However, the treatment
with BMS-191563 did not result in a redistribution of particulate Ras
to the cytosolic fraction, despite the attenuation of agonist-mediated
-ADR downregulation. By contrast, in cultured neonatal rat cardiac
fibroblasts, BMS-191563 treatment inhibited Ras farnesylation
(7). A possible explanation for the disparate action of
BMS-191563 observed between cardiac fibroblasts and skeletal muscle may
be linked to a tissue-specific pattern of Ras isoform expression.
Recent studies have demonstrated that the N and K isoforms of Ras are
substrates for both farnesyl and geranylgeranyl protein transferases
(29, 32). Although Ras isoform distribution in either the
soleus or gastrocnemius muscles is presently unknown, it is possible
the particulate Ras identified in the BMS-191563-treated rats is
geranylgeranylated. Indeed, this alternative processing of Ras isoforms
has been suggested to contribute in part to the resistance of some
cancer cell lines to farnesyltransferase inhibitors (14).
An alternative explanation may reside within the intrinsic turnover
rate of individual farnesylated proteins, as the proteins implicated in
-ADR downregulation may have a faster turnover rate of farnesylation
compared with Ras and, in this regard, would exhibit a greater
sensitivity to the action of BMS-191563. Last, although it is our
contention that BMS-191563 has abrogated -ADR downregulation via the
inhibition of a farnesylated protein, a nonspecific effect of this drug
on a nonfarnesylated protein involved in receptor
sequestration/downregulation cannot be excluded. Consequently,
regardless the mechanism of action, BMS-191563 represents an important
pharmacological tool to elucidate the underlying events implicated in
-ADR downregulation.
Perspectives
This study highlighted a novel action of the farnesyltransferase inhibitor BMS-191563, as this drug attenuated agonist-mediated-ADR
downregulation in both skeletal muscle and cardiac fibroblasts. These
data are consistent with the observation that several well-defined proteins implicated in the homologous desensitization of the -ADR are substrates of the enzyme farnesyltransferase. Clinically, a
plethora of studies has examined the role and regulation of -ADRs in
cardiovascular disease states. In the setting of congestive heart
failure, enhanced sympathetic activity and the secondary desensitization/downregulation of -ADRs in the myocardium have been
suggested to contribute in part to diminished cardiac function (30). Moreover, in the setting of hypertension, the loss
of vasodilatory and antiproliferative action of the -adrenergic system represents an underlying mechanism contributing in part to
enhanced vascular tone and adverse remodeling (9). In this regard, counteracting -ADR downregulation may represent a
therapeutic approach to partially ameliorate various cardiac disease
states. Thus, based on the observations of the present study,
additional studies examining the potential therapeutic benefit of
BMS-191563 and/or an alternative farnesyltransferase inhibitor on
-ADR reactivity in animal models of cardiac disease warrants further
investigation. However, because of the growth-suppressing action of
farnesyltransferase inhibitors in numerous cell types (4, 7,
31), identifying the specific farnesylated target(s) of
BMS-191563 is crucial to selectively inhibit -ADR downregulation.
These latter data may provide the impetus to design pharmacological
strategies that could directly abrogate -ADR downregulation in vivo.
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ACKNOWLEDGEMENTS |
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The contributions of R. J. L. Murphy (School of Recreation and Management and Kinesiology, Acadia University, Nova Scotia); J.-L. Gauthier, P. Corriveau (Dept. of Kinesiology, University of Montreal), and F. Colombo (Institut de Cardiologie de Montreal) are gratefully acknowledged. We also want to thank C.. Laurent (Dept. of Pharmacology, Faculty of Medicine, University of Montreal) for assistance.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Calderone, Institut de Cardiologie, 5000 rue Bélanger E, Montréal, Québec, Canada H1T 1C8 (E-mail: calderon{at}icm.umontreal.ca).
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.
10.1152/ajpregu.00274.2001
Received 15 May 2001; accepted in final form 2 October 2001.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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