Originally published online as doi:10.1189/jlb.0606373 on August 30, 2006
Published online before print August 30, 2006
(Journal of Leukocyte Biology. 2006;80:1214-1221.)
© 2006
by Society for Leukocyte Biology
GRKs and arrestins: regulators of migration and inflammation
Anne Vroon,
Cobi J. Heijnen1 and
Annemieke Kavelaars
Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands
1 Correspondence: University Medical Center Utrecht, Department of Psychoneuroimmunology, Room KC03.063.0, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. E-mail: c.heijnen{at}umcutrecht.nl
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ABSTRACT
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In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.
Key Words: chemokine • chemoattractant • GPCR • desensitization • signaling • inflammatory disease
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THE GRK/ARRESTIN MACHINERY
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The superfamily of seven-transmembrane-spanning G protein-coupled receptors (GPCRs) represents the largest and most versatile of the families of membrane receptors found in nature. In the immune system, triggering of GPCRs is important for multiple activities, including cellular differentiation/activation, development of lymphoid tissue, and especially, for control of leukocyte chemotaxis. GPCR responsiveness is determined by a tightly regulated balance among receptor signaling, desensitization, and resensitization. Receptor desensitization, the waning of GPCR responsiveness to the agonist with time, is an important, physiological "feedback" mechanism that protects against acute and chronic receptor overstimulation [1
]. The protein families of GPCR kinases (GRKs) and arrestins play a pivotal role in the process of desensitization of agonist-activated GPCRs [1
2
3
4
] (Fig. 1
). There are seven known GRK subtypes, of which four members are expressed ubiquitously (GRK2, -3, -5, and -6) [1
, 4
]. In the arrestin family, two members are restricted to photoreceptors, whereas β-arrestin-1 and β-arrestin-2 are expressed ubiquitously [1
]. Agonist-induced desensitization of GPCRs occurs via a multistep process. First, GRKs phosphorylate the intracellular loops and/or carboxyl terminal tail of the receptor, a process that enhances the affinity of the receptor for binding of cytosolic arrestin proteins. Subsequent binding of phosphorylated receptors by arrestins sterically inhibits interaction of the receptor with the G protein. Thus, agonist-induced phosphorylation of GPCRs by a GRK, followed by binding of arrestins, efficiently prevents further coupling of the receptor to its G protein, thereby reducing or preventing receptor signaling [5
] (Fig. 1)
. Finally, the GRK-arrestin system promotes clathrin-mediated internalization of inactivated receptors to endosomal compartments for subsequent degradation or resensitization [1
, 3
, 5
, 6
].
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Figure 1. Schematic summary of the role of GRKs/arrestins in activation, signaling, and desensitization of GPCRs in the immune system. Agonist-activated GPCRs are phosphorylated rapidly by GRKs, leading to recruitment of arrestins. This process, called homologous desensitization, prevents further coupling of the receptor to its G protein, thereby reducing or preventing receptor signaling. In addition, GRKs and arrestins can also act as signal transducers in various signaling pathways. PLC, Phospholipase C; P, phospho group.
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It is notable that besides its role in desensitization, β-arrestin-mediated receptor internalization can also regulate signal transduction. The internalized GPCR-β-arrestin complex can form a signalosome that activates signaling proteins such as ERK1/2, p38 MAPK, and JNK. In addition, arrestins act as scaffolds that connect activated GPCR with tyrosine kinase c-Src and the PI-3K-AKT and NF-
B pathways [7
, 8
] (Fig. 1)
.
GRKs display activities well beyond their classical role in receptor phosphorylation as well. For example, GRKs have been shown to interact with PI-3Ks and a guanosinetriphosphatase (GTPase)-activating protein, GIT1, which are involved in regulating receptor trafficking and signaling [9
, 10
]. In addition, GRK2 interacts with a component of the MAPK pathway, MEK, as well as with the PI-3K substrate AKT [11
, 12
]. Furthermore, GRK2 and -3 are well-known to bind the Gβ
subunit complex, a process that induces activation of these GRKs. In addition, direct interaction of GRKs with G proteins is suggested by the presence of regulator of G protein signaling (RGS)-like domains (RH domains) in GRKs [13
14
15
]. RGS proteins act as GTPase-activating proteins (GAPs), which induce hydrolysis of guanosine 5'-triphosphate (GTP) and thereby inactivation of GTP-bound G
subunits [16
, 17
]. Selective binding of activated G-q (and G-11) to RH domains of GRK2 and GRK3 (but not to RH domains of GRK1 and -4) was found to selectively inhibit Gq signaling. However, as GRK2/3 were shown not to act as GAPs for Gq [13
14
15
, 18
], the main role of RH domains in GRK2/3 appears to prevent activated Gq from interacting with downstream effector molecules.
GRKs and arrestins also interact with non-GPCRs. For instance, GRKs and arrestins interact with TGF-β, epidermal growth factor (EGF), and insulin growth factor receptors [19
20
21
]. In addition, β-arrestin was found to regulate activity of Notch, an important protein in neurogenesis, angiogenesis, and lymphoid development [22
]. GRKs and arrestins may directly affect functioning of these non-GPCRs or modulate signaling of these receptors indirectly. Transactivation of growth factor receptors, such as the EGF receptor by GPCRs such as the β2-adrenergic receptor, CXCR4 chemokine receptor, or PGE2 receptor, has been described extensively [23
24
25
]. Hence, GRK/arrestin-mediated regulation of GPCR signaling may indirectly affect signaling of such growth factor receptors. It is interesting that a recent study shows that formation of a prostaglandin E receptor 4/β-arrestin-1/c-Src signaling complex in colorectal carcinoma cells is a crucial step in PGE2-mediated transactivation of the EGF receptor, indicating that arrestins also directly regulate the transactivation of a growth factor receptor by a GPCR agonist [25
].
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DYNAMIC REGULATION OF GRK/ARRESTIN EXPRESSION IN INFLAMMATION
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The extent of agonist-induced GPCR signaling and desensitization is modulated by the expression level of GRKs and β-arrestins [26
, 27
]. Thus, one of the means to regulate GPCR activity will be through modulation of expression of these proteins. It is intriguing that GRK2, -3, -5, and -6 are expressed at particularly high levels in cells of the immune system [28
]. Moreover, levels of GRKs in immune cells are dynamically regulated, suggesting an important role for these kinases in regulation of immune activity. The activity of cytosolic GRK and the expression of GRK2 and GRK5 are elevated in the lung of IL-1β-treated rats, an effect that is completely abolished by treatment with the anti-inflammatory steroid dexamethasone [29
]. Profound changes in GRK expression have also been described during several inflammatory pathologies in humans and animals. PBMC of patients with rheumatoid arthritis (RA) or multiple sclerosis (MS) show significant down-regulation of GRK2 and GRK6 expression [30
31
32
]. Similarly, GRK2 and GRK6 protein levels are reduced markedly in immune organs from rats with chronic relapsing experimental autoimmune encephalomyelitis (EAE) and in immune cells from rats with experimental adjuvant arthritis [33
, 34
]. The inflammatory activity during arthritis affects GRK expression only in cell subsets that are involved in the disease: CD4+ T cells and B cells, but not CD8+ T cells [34
].
Inflammatory mediators such as oxygen radicals and proinflammatory cytokines are capable of reducing GRK2 protein in vitro [32
, 35
]. LPS-induced signaling through the TLR4 pathway down-regulates chemokine-induced expression of GRK2 and GRK5 in polymorphonuclear neutrophils (PMN) [36
]. In aortic smooth muscle cells, IL-1, TNF-, and IFN- were found to regulate GRK2 expression at the transcriptional level by decreasing the activity of the GRK2 promoter [37
]. Conversely, calpain-dependent degradation was observed to be involved in down-regulation of GRK2 in lymphocytes in response to cytokines and oxygen radicals [35
]. As circulating levels of these mediators are well known to be increased in RA and MS/EAE [38
39
40
41
], these mediators are likely to be responsible for the observed reduction in GRK expression in the immune system during the disease.
It is interesting that down-regulation of GRK2 and GRK6 during inflammatory disease does not reflect an overall reduction in components of the GPCR desensitization machinery, as protein expression of β-arrestin-1 is not changed in PBMC from patients with RA [32
]. Moreover, β-arrestin-1 levels were even increased in immune cells during myelin oligodendrocyte glycoprotein (MOG)-EAE and adjuvant arthritis in animals [33
, 34
].
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GRK AND ARRESTINS AS REGULATORS OF INFLAMMATORY DISEASE
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Down-regulation of GRK levels in immune cells during inflammatory disease may represent an adaptation mechanism of cells responding to a disease state but may also be maladaptative and could contribute to disease progression. In fact, the potential maladaptive effects of alterations in GRK levels have been demonstrated in the cardiovascular system. Targeted overexpression of GRK2 in vascular smooth muscle induces hypertension and cardiac hypertrophy [42
], implicating the vital importance of "normal" GRK2 levels for vascular control.
Increasing evidence obtained from studies in animal models points toward a regulatory role of the GRK-arrestin machinery in development and progression of inflammatory diseases as well. For instance, we have shown that a 50% reduction in GRK2 protein in GRK2+/– mice profoundly affects the clinical course of chronic relapsing, MOG-induced EAE, an animal model for multiple sclerosis, which is characterized by infiltration of inflammatory T cells into the CNS. Heterozygous GRK2 knockout (KO) animals, which have a 50% decrease in GRK2 protein levels, show a significantly advanced onset of disease, associated with a higher number of inflammatory, cellular infiltrates in the spinal cord [30
]. Although the onset of the first peak of disease activity in this relapsing-remitting disease model was advanced in GRK2+/– animals, the reduction in GRK2 was associated with a milder course of the relapsing-remitting phase of the disease. In fact, in this study, GRK2+/– animals did not develop significant relapses during the 48 days of the study but gradually recovered from the disease, whereas wild-type animals developed multiple relapses [30
].
It is important that changes in expression of GRKs not only affect acquired (auto)immune responses but can also alter the extent of acute (innate) inflammatory processes. In two in vivo models, GRK6 was found to regulate neutrophil migration and mobilization. Acute ear inflammation in response to topical application of arachidonic acid (AA) is increased markedly in GRK6–/– and GRK6+/– animals, both at the level of edema formation as well as at the level of neutrophil infiltration into the ear [43
]. However, PMA-induced ear edema and neutrophil influx are not altered in GRK6–/– mice, suggesting that the increased inflammatory response in GRK6–/– ears is specific for AA metabolites and does not reflect a general enhancement of neutrophil chemotactic activity in the absence of GRK6 [43
].
In contrast, absence of GRK6 was shown to negatively affect neutrophil mobilization from the bone marrow. Under normal conditions, neutrophils are released from the bone marrow into the circulation in a highly regulated manner, involving disruption of key retention signals [44
45
46
]. Mobilization of neutrophils into the blood in response to administration of pegylated G-CSF (peg-G-CSF) was impaired severely in GRK6–/– mice [47
]. peg-G-CSF-induced production of neutrophils in the bone marrow was normal, suggesting that absence of GRK6 promotes retention of cells in the bone marrow.
Besides GRKs, also β-arrestin has emerged as a possible regulator of neutrophil- and T cell-mediated inflammatory responses. For instance, β-arrestin is involved in the regulation of chemokine-induced granule release [48
] as well as in CXCR2-mediated neutrophil recruitment in two models of inflammation: the dorsal air-pouch model and the cutaneous wound-healing model [49
]. In addition, a recent study by Walker et al. [50
] describes a critical role for β-arrestin-2 in regulation of the inflammatory process associated with allergic asthma, which is a chronic, inflammatory disorder of the airways, coordinated by Th2 cells in human asthmatics and animal models of allergic asthma. In contrast to wild-type mice, allergen-sensitized mice with a targeted deletion of the β-arrestin-2 gene do not accumulate T lymphocytes in their airways nor do they demonstrate other physiological and inflammatory features of asthma [50
]. The airway inflammatory response to LPS, which is not controlled by Th2 cells, is fully functional in mice lacking β-arrestin-2. In addition, β-arrestin-2-deficient mice have normal OVA-specific IgE responses but defective macrophage-derived, chemokine-mediated CD4+ T cell migration to the lung [50
]. These data not only implicate the requirement of β-arrestin-2 for the manifestation of allergic asthma but also suggest that β-arrestin-2 contributes to the regulation of inflammatory cell migration. Not only β-arrestin-2 but also β-arrestin-1 was found to regulate cellular migration. In a study by Buchanan et al. [25
], interactions of β-arrestin-1 with c-Src and the prostaglandin E receptor 4 were observed to be crucial for regulation of colorectal carcinoma cell migration in vitro as well as metastatic spread of disease to the liver in vivo [25
].
In conclusion, these in vivo studies suggest an important physiological role for GRK2, GRK6, and β-arrestin-1 and -2 in regulation of inflammatory activity, presumably via influencing leukocyte trafficking.
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REGULATION OF CHEMOKINE RESPONSES BY GRKs/ARRESTINS
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During inflammatory diseases, increased signaling of chemokine receptors contributes to disease pathology, modulating directed migration, and activation of T cells, monocytes, and neutrophils. Overexpression studies have shown a prominent role of GRK2 in phosphorylation, desensitization, and internalization of chemokine receptors such as CCR5 and CCR2b [51
52
53
54
]. The involvement of these chemokine receptors in migration of inflammatory T cells to the nervous system during the onset of EAE has been well established [55
56
57
58
59
]. Using T cells of GRK2+/– mice, we clearly demonstrated that low GRK2 significantly enhances CCR5 agonist-induced calcium mobilization, signaling to protein kinase B (PKB) and ERK1/2, as well as directed migration of these cells to CCR5 agonists in vitro [60
] (Table 1
). Similarly, CCR2-mediated signaling to ERK1/2 is increased in GRK2+/– splenocytes [11
]. Enhanced chemokine responsiveness may well explain the earlier onset of EAE in GRK2+/– animals. As mentioned above, a significantly higher number of inflammatory cell infiltrates were observed in the spinal cord of GRK2+/– early after EAE induction, supporting the hypothesis that GRK2 regulates recruitment of inflammatory cells via receptors such as CCR5 and CCR2b [30
].
Similar to GRK2, GRK6 also inhibits chemokine/chemoattractant receptor signaling (Table 1)
. GRK6–/– neutrophils show more prolonged LTB4-induced calcium mobilization and actin polymerization, suggesting that responsiveness of BLT-1, the LTB4 receptor, is enhanced in the absence of GRK6 [43
]. Consistent with this finding, overexpression of GRK6 has been shown to promote ligand-induced desensitization of BLT-1 in COS-7 cells [64
]. Furthermore, chemotactic responses to the BLT-1 agonist LTB4 are increased profoundly in GRK6–/– PMN [43
]. As LTB4 mediates the response to AA, including ear swelling and neutrophil infiltration [65
, 66
], enhanced BLT-1 responsiveness of GRK6–/– may well explain the enhanced AA-induced ear inflammation observed in these animals.
GRK6 also regulates the responsiveness of CXCR4. Absence of GRK6 is associated with enhanced stromal cell-derived factor-1 (SDF-1)-induced GTPase activity in splenocytes [61
], as well as with increased SDF-1-induced chemotaxis and calcium responses of neutrophils [47
]. Signaling via CXCR4 controls a wide variety of physiological processes, which includes regulation of stem-cell homing and neutrophil mobilization. In the bone marrow, the SDF-1/CXCR4 chemotactic axis represents a key retention signal for neutrophils/hematopoietic progenitors, and disruption of CXCR4 signaling is considered an important mechanism to induce cell mobilization in response to growth factors such as G-CSF [44
45
46
]. In view of these data, the observed, impaired mobilization (or enhanced retention) of GRK6–/– neutrophils in response to G-CSF may likely result from enhanced responsiveness of CXCR4 in these animals. In view of these findings and knowing that neutrophils have a crucial role in various infectious and inflammatory diseases, regulation of GRK6 expression during infection/disease may be an important mechanism to modulate disease progression, via changes in neutrophil migration/mobilization. Other GRKs may regulate neutrophil responses as well, as was demonstrated by Fan and Malik [36
]. These authors showed that TLR-mediated down-regulation of GRK2 and GRK5 is associated with augmentation of IL-8/growth-related oncogene- (CXCR2)-induced neutrophil migration [36
].
It is of interest to note that the increased chemotactic response to SDF-1 in the absence of GRK6 is neutrophil-specific. T cells from GRK6-deficient mice are impaired in their ability to migrate in response to SDF-1, whereas lymphocytes from GRK5 KO animals do not show altered chemotactic activity to this CXCR4 agonist [61
]. Of course, the difference in chemotactic activity between PMN and T cells of GRK6–/– animals could reflect differences in cell type-specific characteristics of the CXCR4 or CXCR4-induced cellular responses. However, it seems more likely that the differences in SDF-1-induced chemotaxis between PMN and T/B cells are a result of differences in cell type-specific mechanisms of migration, which are affected by GRK6. Indeed, it has been suggested that T cells and PMN differ in locomotor behavior during chemotaxis; T lymphocytes increase their locomotion by reducing the duration of migration breaks, and PMN migrate by reducing the frequency of migration breaks [67
]. In addition, chemotaxis-related intracellular regulatory signaling is different between both cell types; e.g., chemotaxis of T cells is dependent on both protein tyrosine kinase and PKC activity, whereas neutrophil chemotaxis mainly involves PKC activity [67
]. Whether these differences are related to differences in regulation of chemotaxis by GRK6 remains to be established.
It is notable also that arrestins have been found to positively regulate chemokine responsiveness (Table 1)
. Recent studies demonstrate the requirement of β-arrestin-2 for constitutive PAR-2-mediated migration of breast cancer cells [63
]. In addition, in the absence of β-arrestin-2, in vitro CXCR4-mediated migration of T and B cells is deficient, despite increased signaling [61
]. As discussed before, chemokine-induced migration of Th2 cells to the lung is key to their inflammatory function in allergic asthma. Studies using neutralizing antibodies for the CXCR4 agonist SDF-1 demonstrated the critical involvement of the CXCR4/SDF-1 chemotactic axis in development of lung inflammation and airway hyper-responsiveness [68
]. In view of these data, the absence of asthmatic features such as inflammatory T cell accumulation in allergen-treated β-arrestin-2 KOs may reflect impaired functioning of chemokine receptors such as CXCR4. These studies therefore suggest a role for β-arrestin-2 in supporting chemokine-induced trafficking of leukocytes during disease.
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GRK AND ARRESTINS: MULTIPLE ROLES IN CHEMOTACTIC SIGNALING
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There are multiple possible mechanisms via which GRKs/arrestins can modulate chemotactic activity. Low levels of GRK can result in increased receptor signaling and thereby increased migration. However, it is of interest to mention that GRK2 has been shown to bind and phosphorylate several nonreceptor substrates, including synuclein [69
], phosducin [70
], ezrin [71
], and tubulin [72
, 73
]. In view of the important role of chemoattractant-induced cytoskeletal rearrangements in cellular motility [74
, 75
], GRK2 might regulate chemotactic activity via effects on the actin cytoskeleton or tubulin/microtubules. Although it is still unclear whether phosphorylation by GRK2 alters tubulin polymerization, functional interactions between GRK2 and tubulin may locally affect microtubule dynamics that regulate migration [72
, 76
].
In addition, the contribution of GRK2 in agonist-induced recruitment of PI-3K to the membrane signifies a possible role for GRK2 in modulation of the PI-3K pathway, whose importance in cellular motility has been well established [9
]. Fan and Malik [36
] recently described the ability of MIP-2 to induce GRK2 (and GRK5) expression in neutrophils via a PI-3K-dependent pathway, a process that may contribute to feedback control of chemotactic activity. In addition, Liu et al. [12
] reported a physical interaction of GRK2 with AKT in sinusoidal, endothelial cells, which results in inhibition of AKT activity. In short, tightly regulated interactions between GRK2 and the PI-3K pathway may serve to control the activity of these kinases, thereby modulating chemotactic responses of immune cells (Fig. 2
). Finally, GRK2 has been found also to directly affect MAPK signaling. Recent data suggest an important role for GRK2 in the control of CCR2-induced ERK activation at the level of the MEK-ERK interface [11
].
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Figure 2. Schematic summary of signaling pathways modulated by GRKs and arrestins, relevant for inflammation.
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Although increased receptor signaling may lead to increased chemotaxis, it has also been shown that β-arrestin-2-deficient T/B cells display impaired chemotactic activity despite enhanced GTPase activity [61
]. Possibly, arrestin-mediated receptor internalization followed by re-expression is required to continue to sense the chemokine gradient during the migration process. Alternatively, altered migratory capacity results from processes independent of (classical) receptor desensitization (Fig. 2)
. As discussed before, arrestins are acknowledged to be multifunctional adaptors and signal transducers, connecting activated receptors with diverse signaling pathways in the cell, including MAPK. For example, intracellular signaling to ERK1/2 in response to stimulation of CCR7 or PAR2 was shown to require β-arrestin-2 [77
, 78
]. Moreover, studies about PAR2 signaling suggest the involvement of a β-arrestin/ERK1/2 signaling complex in reorganization of the actin cytoskeleton, which promotes chemotaxis [79
]. Thus, the ability of arrestins to interact with and activate MAPKs may play a distinct role in chemotactic activity of cells, which may also explain the data, suggesting that the absence of β-arrestin-2 impairs CXCR4-mediated migration of T and B cells [61
]. Indeed, in HEK293 and HeLa cells, β-arrestin-2 augments SDF-1-induced chemotaxis via enhancement of p38 MAPK activation [62
].
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CONCLUSIONS AND PERSPECTIVES
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Increasing data reveal a crucial role of GRK and arrestins in regulating different aspects of inflammation, such as chemokine-induced migration and mobilization of inflammatory cells. It is traditional that GRKs/arrestins were thought to be involved in protective mechanisms of regulation, controlling GPCR signaling and preventing overstimulation of cells. However, when expression of these factors is altered, as is occurring during inflammatory diseases, these mechanisms may also be maladaptive and may participate in disease progression.
The observed, marked effects of specific alterations in the level of expression of one GRK and/or arrestin on disease progression and sensitivity of chemokine receptors are particularly interesting in view of previous in vitro studies about GRK-GPCR specificity. Overexpression studies in cultured cells have suggested that the various GRKs are functionally redundant with respect to the phosphorylation and desensitization of, for instance, CCR5 and BLT-1 [52
, 64
]. Obviously, levels of GRKs obtained by overexpression do not reflect expression levels in the diverse, physiological environments. The recent studies performed in KO animals strongly indicate that defined roles for each of the GRKs/arrestins exist and that there may be a higher degree of specificity for the GPCR-GRK interaction than was anticipated from transfection studies. It is remarkable that even a relatively small reduction in GRK expression (50% in GRK2 or GRK6 heterozygous animals) already results in significant changes in receptor signaling and chemotaxis in vitro [60
] and profoundly affects inflammation in vivo [30
, 43
].
In conclusion, responsiveness of an immune cell is not only dictated by the level of a certain inflammatory mediator and the expression of its receptor but also by the mechanisms that regulate receptor responsiveness and signaling. The importance of GRKs and arrestins in regulation of chemokine-mediated responses reveals a mechanism previously unacknowledged that controls or regulates immune activity. Especially during inflammatory disease, alterations in expression and activity of GRKs and arrestins should be taken into account when GPCR-mediated responses are studied or targeted therapeutically. Clearly, further studies in gene-targeted animals are of great importance for our understanding of the role of GRKs/arrestins in receptor desensitization and signal propagation in inflammatory disease. In addition, analysis of the specific mechanisms that govern GRK/arrestin expression during inflammatory disease is needed. In the end, these studies may provide a basis for the definition of new, therapeutic targets aimed at regulating intracellular GRK/arrestin levels to control inflammatory activity.
Received June 6, 2006;
revised July 21, 2006;
accepted July 25, 2006.
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ABSTRACT
THE GRK/ARRESTIN MACHINERY
