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Hypertension. 2006;48:173-179
Published online before print July 3, 2006, doi: 10.1161/01.HYP.0000232641.84521.92
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(Hypertension. 2006;48:173.)
© 2006 American Heart Association, Inc.

Brief Reviews

Signal Switching, Crosstalk, and Arrestin Scaffolds

Novel G Protein–Coupled Receptor Signaling in Cardiovascular Disease

Nicola J. Smith; Louis M. Luttrell

From the Molecular Endocrinology Laboratory (N.J.S.), Baker Heart Research Institute, Melbourne, Victoria, Australia; Departments of Medicine and Biochemistry and Molecular Biology (L.M.L.), Medical University of South Carolina, Charleston; and the Ralph H. Johnson Veterans Affairs Medical Center (L.M.L.), Charleston, SC.

Correspondence to Louis M. Luttrell, Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, 816 CSB, PO Box 250624, Charleston, SC 29425. E-mail luttrell{at}musc.edu


*    Introduction
up arrowTop
 *Introduction
down arrowG Protein Switching: Why...
 down arrowTransactivation of EGF...
 down arrowNovel G Protein-Independent...
 down arrowReferences
 
Hormone agonists, including angiotensin II (Ang II), norepinephrine, urotensin II, endothelin-1, vasopressin, and serotonin, mediate a plethora of physiological and pathological cardiovascular events via their cognate 7 membrane-spanning G protein–coupled receptors (GPCRs). On ligand binding, GPCRs undergo conformational changes that enable the activation and dissociation of heterotrimeric guanine nucleotide binding proteins (G proteins) and trigger a range of intracellular second messenger signaling cascades. Because of the immediacy of second messenger generation, GPCRs are able to acutely regulate cardiovascular events such as heart rate, contractile force, and systemic vascular resistance. Compelling evidence for GPCR control in the vasculature comes from both transgenic studies and clinical findings. For example, ß-adrenergic receptor blockers and inhibitors of the synthesis and binding of Ang II are proven antihypertensive therapeutics for humans. Furthermore, mice lacking RGS2, a regulatory protein that enhances the speed of GPCR signal termination, display marked hypertension, increased basal vascular tone, and hypersensitivity to vasoconstrictive agonists,1 a phenotype that demonstrates the contribution of immediate GPCR-dependent signals, as well as the effect of GPCR dysregulation on cardiovascular homeostasis.

The evidence that signals emanating from GPCRs also contribute to the chronic development of vascular disease is persuasive. Overexpression of the G{alpha}q subunit in cardiomyocytes directly stimulates cardiac hypertrophy and decompensated heart failure,2 whereas transgenic mice expressing an inhibitory fragment of G{alpha}q exhibit reduced hypertrophy in response to pressure overload.3 GPCR agonists like Ang II, endothelin-1, and norepinephrine, act directly on cardiomyocytes to stimulate hypertrophy.4 Meanwhile, Ang II contributes to atherosclerosis via activation of vascular smooth muscle cell (VSMC) migration and hypertrophy; this occurs either directly, via the Ang II type 1 receptor (AT1R), or indirectly by stimulating endothelin-1 expression or activating inflammatory pathways.5 Importantly, these pathological vascular effects require significant modulation of gene transcription, often via activation of growth-promoting mitogen-activated protein kinase (MAPK) cascades.

A confounding issue in GPCR biology has been the incongruity between acute second messenger signals generated by ligand binding and longer-term changes in gene expression and cell growth. Indeed, studies over the past decade have demonstrated that GPCR signaling is more complicated than predicted by the ternary complex model of receptor–G protein–effector signaling. Receptor coupling specificity can be modified by phosphorylation, not only quantitatively in terms of desensitization, but also qualitatively via G protein "switching." Many, if not most, GPCRs engage in crosstalk with receptor tyrosine kinases (RTKs). Transactivation of epidermal growth factor (EGF) receptors allows GPCRs to initiate Ras-dependent signals that control gene expression and stimulate cell proliferation. Interactions with accessory/scaffold proteins, such as arrestins, which recruit signaling and adaptor proteins to the receptor, confer novel enzymatic activity and permit GPCRs to generate G protein–independent signals. In this review, we describe these novel mechanisms of GPCR signal transduction and discuss evidence that suggests that they may have important roles in the pathogenesis of cardiovascular disease.


*    G Protein Switching: Why Do ß1 and ß2 Adrenergic Receptors Seem to Play Opposing Roles in Cardiac Adaptation?
up arrowTop
 up arrowIntroduction
 *G Protein Switching: Why...
down arrowTransactivation of EGF...
 down arrowNovel G Protein-Independent...
 down arrowReferences
 
Although acute release of catecholamines is an adaptive mechanism whereby heart rate and contractile force are increased to meet an imminent threat, the chronic exposure to excess catecholamines characteristic of heart failure is clearly maladaptive.6,7 Within the failing ventricle, increased sympathetic tone desensitizes the ß-adrenergic receptor system and engenders changes in the expression of receptors and regulatory proteins that decrease catecholamine responsiveness, while at the same time initiating signals that promote cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis. Mice that are unable to synthesize norepinephrine because of targeted disruption of the dopamine ß-hydroxylase gene exhibit less cardiac hypertrophy and preserved ventricular function after surgical constriction of the transverse aorta, directly demonstrating the deleterious effects of sustained catecholamine excess.8 Accordingly, several large clinical trials have shown the survival benefit of ß blockers in moderate-to-severe heart failure.9–11

Although cardiomyocytes express both ß1 and ß2 adrenergic receptors, and both acutely increase cardiac contractility by enhancing cAMP-mediated signaling, the 2 subtypes appear to have different effects in the failing ventricle. Even modest cardiac overexpression of ß1 receptors leads to cardiomyocyte hypertrophy, loss of cardiomyocytes, cardiac fibrosis, and heart failure in mice.12,13 In contrast, ß2 receptor overexpression produces cardiac pathology only at very high levels and at lower levels (30- to 50-fold) improves cardiac contractility with no deleterious effects.14,15 In cultured cardiomyocytes, ß1 receptor stimulation is directly proapoptotic, whereas ß2 receptors exert antiapoptotic effects.16,17 Several hypotheses have been advanced to account for these striking functional differences. Although ß2 receptors cause more adenylyl cyclase stimulation than ß1 receptors, activation of cardiac ß1 receptors produces larger functional effects, leading to speculation that they generate functionally discrete cAMP pools. Differential compartmentation of receptor subtypes in caveolae, assembly of receptors and their effectors into preorganized signalsomes, and differences in the kinetics of receptor desensitization may all contribute to their functional specialization.7 Another possible explanation arises from the observation that ß2 receptors are able to activate nonclassical signaling pathways by coupling to pertussis toxin–sensitive Gi proteins through a phosphorylation-dependent switch in receptor–G protein–coupling selectivity that occurs as the receptor desensitizes.18

Desensitization of GPCRs begins within seconds of agonist exposure and is initiated by phosphorylation of the receptor. Second messenger–dependent protein kinases, including protein kinase (PK) A and PKC, phosphorylate serine and threonine residues within the cytoplasmic loops and C-terminal tail domains of many GPCRs. Phosphorylation of these sites directly impairs receptor–G protein coupling. Because agonist occupancy of the target GPCR is not required for phosphorylation, and receptors for different ligands can be affected simultaneously, this process is often referred to as heterologous desensitization. Heterologous desensitization is distinguishable from homologous desensitization, which is a 2-step process involving the phosphorylation of an agonist-activated GPCR by a GPCR kinase, followed by binding of an arrestin protein that uncouples receptor and G protein. Homologous desensitization is selective for agonist-occupied receptors and in nonvisual tissues is usually followed by endocytosis of the GPCR–arrestin complex.19

In some cases, notably the ß2-adrenergic and murine prostacyclin receptors, PKA phosphorylation also alters the G protein–coupling selectivity of the receptor to favor coupling to the adenylate cyclase inhibitory Gi protein over the stimulatory Gs protein, causing the PKA-phosphorylated receptor to "reverse direction" with respect to cAMP production.20–22 The phosphorylation-induced switch in G protein coupling also provides the receptor access to alternative signaling pathways, leading, for example, to Gi-dependent activation of MAPK. In cardiomyocytes, ß2, but not ß1, receptors promote cell survival through a pertussis toxin–sensitive pathway involving Gi, phosphatidylinositol 3-kinase, and Akt, suggesting a mechanism whereby G protein switching might contribute to the protective effect of ß2 receptors observed in murine heart failure models.17,23 Although this in vitro and animal work suggests a rationale for the use of ß1-selective blockers in the clinical management of congestive heart failure, data from human trials have yet to definitively establish the optimal activity profile for ß blockers. Both the ß1 receptor–selective antagonists Metoprolol and Bisoprolol, and the nonselective ß1, ß2, and {alpha}1 adrenergic receptor blocker Carvedilol have demonstrated clinical survival benefit.9–11 Although the recent Carvedilol or Metoprolol European Trial (COMET) trial found superior survival benefit for Carvedilol over an immediate-release form of Metoprolol, a head-to-head comparison of sustained-release preparations of selective versus nonselective ß blockers is lacking, leaving significant questions about the role of ß2 receptor signaling in the failing ventricle and the net benefit of selective versus nonselective ß blockers in human disease.24,25


*    Transactivation of EGF Receptors: A Common Pathway for GPCR-Stimulated Cell Growth and Proliferation?
up arrowTop
 up arrowIntroduction
 up arrowG Protein Switching: Why...
 *Transactivation of EGF...
down arrowNovel G Protein-Independent...
 down arrowReferences
 
An unresolved question in vascular biology is how diverse stimuli, acting through structurally distinct membrane receptors, are often able to evoke a common set of cellular responses. For polypeptide growth factors that bind to classical growth factor RTKs, including the EGF and platelet-derived growth factor receptors, the general mechanisms leading to cellular growth are well understood.26 Several such factors, produced and released from the vessel wall or activated cells of the immune system, have been implicated in the development of vascular disease in hypertension and/or diabetes mellitus.27,28 These growth factors bind to receptors on vascular cells and initiate tyrosine kinase signaling cascades that lead to cell proliferation, differentiation, or apoptosis. What is less clear is how ligands that interact with GPCRs or cytokine receptors that lack intrinsic tyrosine kinase activity and even GPCR-independent stimuli, such as reactive oxygen species (ROS), gain access to the same growth regulatory pathways. The discovery that many otherwise distinct extracellular stimuli share the ability to "transactivate" EGF receptor (EGFR) family RTKs (EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 receptors) has lead to the hypothesis that ErbB receptors serve as a convergence point in cell growth control.29

Since the phenomenon was initially described,30 numerous GPCRs have been shown to usurp the signaling machinery of ErbB receptors to induce Ras-dependent MAPK activation and stimulate phosphatidylinositol 3-kinase–dependent cell survival. Although ErbB transactivation was initially thought to be an intracellular process,30 subsequent work elegantly demonstrated that in most cases transactivation results from GPCR-stimulated release of EGF-like ligands, leading to activation of ErbB receptors in an autocrine or paracrine manner.31 EGF family growth factors are synthesized as transmembrane precursors, and most must be cleaved to generate a mature ligand.32 It is this processing step that allows external stimuli to transactivate ErbB receptors. The regulated release of EGF family growth factors is carried out by proteases of the ADAM (a disintegrin and metalloprotease) family. Unlike most Zinc-binding matrix metalloproteases, which are secreted proteins, ADAMs are membrane-anchored proteases that catalyze ectodomain shedding either constitutively or on activation by extracellular stimuli. Once liberated, EGF family growth factors bind to monomeric ErbB receptors and promote receptor dimerization/oligomerization and transphosphorylation of the cytoplasmic tyrosine kinase domains.26 The fact that ErbB1–4 receptors can form either homodimers or heterodimers means that several functionally distinct signaling platforms can be generated after stimulation with a single ligand. Depending on the specific EGF family growth factor(s) produced and the combinations of ErbB1–4 homodimers and heterodimers that form, EGF receptor activation can trigger cell proliferation, differentiation, apoptosis, or migration and induce the expression of target genes, among them other peptide growth factors.

Evidence of a fundamental role for ErbB receptor transactivation in cardiovascular homeostasis and pathology comes from both genetic and pharmacological studies.33–35 Mice lacking EGFR, ErbB2, or heparin-binding (HB)-EGF all develop cardiac hypertrophy and cardiomyopathy, whereas a subset of patients treated for EGFR-positive breast cancer with the ErbB2 antagonist Herceptin developed dilated cardiomyopathy. Ang II has been shown to transactivate the EGFR in isolated cardiomyocytes36 and whole hearts, the latter study suggesting that ADAM12 was responsible for HB-EGF shedding and subsequent cellular hypertrophy.37 Although not necessarily the sole signaling pathway by which GPCRs stimulate cardiomyocyte hypertrophy, urotensin II,38 endothelin-1,37 purinergic P2Y,39 and {alpha}1-adrenergic39 receptors all stimulate cardiac enlargement via an ErbB receptor–dependent mechanism. Studies in renal and VSMCs further illustrate the general importance of transactivation in vascular biology. Endothelin-1 acts acutely via the EGFR to promote vasoconstriction both in isolated aortic rings and in vivo, whereas over time the same pathway can stimulate collagen transcription leading to vascular fibrosis.40 Ang II stimulation of VSMC hypertrophy is undoubtedly the most extensively characterized vascular outcome of EGFR transactivation. Numerous studies by Eguchi et al,41 among others, have shown that Ang II stimulates hypertrophy and migration via metalloprotease-dependent shedding of HB-EGF and subsequent EGFR activation. Furthermore, ROS are critical to transactivation in this context, potentially exacerbating the existing pathological effects of ROS on the vasculature.42 In an experimental model of diabetes, administration of ErbB inhibitors normalized norepinephrine, endothelin-1, and Ang II-mediated vasoconstrictor responses, suggesting that ErbB transactivation contributes to abnormal GPCR regulation of vascular tone in diabetes.43 Furthermore, renal hypertrophy and hyperplasia in streptozotocin-induced diabetic rats can be reduced by ErbB inhibition,44 whereas Ang II modulation of ADAM17-dependent transactivation in chronic kidney disease further confounds cardiovascular pathology.45

Although our understanding of GPCR growth signaling has advanced substantially over the past decade, a number of basic questions persist. For the AT1R, the question of whether G protein activation is necessary for EGFR transactivation remains controversial.46 The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, which is involved in the activation of early growth responses for some GPCRs,47–49 has been suggested to facilitate EGFR transactivation independent of G protein-coupling.50 However, initial reports that Ang II–stimulated transactivation is G protein independent have been refuted in VSMCs and transformed cells by multiple groups.51,52 Still, transgenic mice expressing an "uncoupled" AT1R mutation develop profound cardiac hypertrophy and atrioventricular conduction block, at least suggesting that signals other than G protein–dependent ectodomain shedding contribute to the development of cardiomyopathy.53 Apart from the mechanism of GPCR-mediated ADAM activation, even the identity of the ADAMs that function as physiological sheddases in ErbB transactivation is far from resolved. Phorbol esters are the best characterized activators of ADAM metalloprotease activity, yet most GPCRs do not require PKC for transactivation.36 The strongest genetic argument for a physiological GPCR-regulated sheddase can be made for ADAM17, also known as tumor necrosis factor-{alpha}–converting enzyme (TACE). Mice lacking transforming growth factor (TGF)-{alpha}, HB-EGF, ErbB1, or TACE share phenotypic traits not seen in other knockout lines, such as defects in cardiac development, early eye opening, and wavy whiskers.54–57 In vitro, TACE-deficient cells cannot cleave the immature forms of TGF-{alpha}, HB-EGF, and amphiregulin (AR).58 Nonetheless, different ADAMs cleave specific subsets of EGF family ligands. In a comparison of ectodomain shedding from primary murine fibroblasts lacking specific ADAMs, ADAM10 appears to be required for EGF and betacellulin shedding, whereas ADAM17 is essential for epiregulin, TGF-{alpha}, AR, and HB-EGF.59 The involvement of individual EGF family growth factors in specific physiological and pathological processes is similarly unresolved. Although most studies to date have focused on HB-EGF, at least 5 of the 13 known EGF-like ligands, HB-EGF, TGF {alpha}, AR, betacellulin, and epiregulin, comprising both ErbB1 and ErbB4 ligands, can undergo regulated shedding.59 Because each ligand binds a discrete subset of ErbB receptors and is, thus, capable of forming ErbB homodimers and heterodimers with different response profiles,35 the possibility exists that cell type–specific shedding of different ligands determines the outcome of ErbB transactivation in different contexts.60 Another confounding observation is that Ang II reportedly stimulates formation of a physical complex between the AT1R and EGFR, suggesting that transactivation may occur over short distances in the context of signaling microdomains or multiprotein signaling complexes that could serve to modify the signal output.61 The recent demonstration that activation of a preformed complex between ADAM10 and the Eph3A RTK involves ADAM10-mediated cleavage of a ligand expressed on the surface of neighboring cells raises the possibility that similar events might control ErbB transactivation.62 This notion of conditional or context-specific transactivation resulting from paracrine or juxtacrine signaling remains to be thoroughly explored.


*    Novel G Protein–Independent Signals in the Vasculature: Do ß-Arrestins Function as Alternative GPCR Signal Transducers?
up arrowTop
 up arrowIntroduction
 up arrowG Protein Switching: Why...
 up arrowTransactivation of EGF...
 *Novel G Protein-Independent...
down arrowReferences
 
As mentioned previously, the duration and strength of G protein signaling is limited by homologous desensitization and internalization of GPCRs mediated by the 2 nonvisual arrestin isoforms, ß-arrestins 1 and 2. Because of their ability to bind simultaneously to agonist-occupied GPCRs and elements of the cellular endocytic machinery, ß-arrestins facilitate receptor endocytosis by clustering receptors within clathrin-coated pits. The longevity of the receptor–ß-arrestin interaction is a major determinant of the fate of internalized receptors, with receptors that dissociate from ß-arrestin on endocytosis tending to be rapidly recycled, whereas receptors that form stable complexes are slowly recycled or degraded.63 For some time, negative regulation of G protein signaling was the only known role for ß-arrestins in GPCR regulation. More recently, the discovery that ß-arrestins bind to a number of signaling proteins and can act as ligand-regulated scaffolds has revealed a previously unappreciated level of complexity in GPCR function. Because ß-arrestin binding precludes catalytic interaction between GPCRs and G proteins, ß-arrestin binding could be viewed as switching the receptor between 2 qualitatively, temporally, and spatially distinct signaling modes. Notably, among the catalytically active proteins that are recruited to GPCR-bound ß-arrestins in an agonist-dependent manner include Src family tyrosine kinases, cRaf-1, MEK1, JNK3, the E3 ubiquitin ligase, Mdm2, and the cAMP phosphodiesterase, PDE4D, many of which are critical components of growth pathway activation.64

The most extensively investigated ß-arrestin–dependent signal is activation of the extracellular signal–regulated kinase (ERK)1/2 MAPK cascade. Best characterized is the involvement of GPCR–ß-arrestin "signalsomes" in controlling the function of ERK1/2 activated by the AT1R and lysophosphatidic acid (LPA) receptors. Recent loss of function data using knockdown of ß-arrestin expression with small interfering RNA and cells derived from ß-arrestin 1/2-null mice indicate not only that ß-arrestin–dependent ERK1/2 activation occurs under physiological conditions but also that ß-arrestins can support AT1R-stimulated ERK1/2 activation in the absence of detectable G protein activation.65 Importantly, by switching the receptor from a G protein–dependent mode to a ß-arrestin–dependent mode, the nature of ERK1/2 signaling is altered. Instead of the immediate and robust ERK1/2 phosphorylation and nuclear translocation that results from G protein activation, the ß-arrestin pathway sequesters active ERK1/2 in the cytoplasm, prolonging the duration of ERK1/2 activation and exposing it to a new array of substrates.64 Furthermore, ß-arrestin binding shortens the duration of ERK1/2 activation via G protein–dependent pathways, including EGFR transactivation. In ß-arrestin 1/2 null fibroblasts stimulated with LPA, reintroduction of ß-arrestin 2 leads to a second wave of ERK1/2 signaling transmitted through ß-arrestin while concurrently shortening the period of transactivation-dependent signaling.66 Interestingly, the strength of receptor–ß-arrestin interaction may dictate the ability of ERK1/2 activated through the ß-arrestin pathway to elicit a transcriptional response, although at present gene array studies exist only for the transient ß-arrestin–binding LPA receptor.66,67

If ERK1/2 transcriptional activity is attenuated or even abolished by cytoplasmic sequestration of ß-arrestin–bound ERK1/2, what function might ß-arrestin–dependent signaling pathways serve? Other than acting to limit nuclear consequences of ERK1/2, such as cellular proliferation,67 cytoplasmic ERK1/2 is known to actively promote a variety of physiological responses including apoptosis and changes in the cytoskeleton, cell shape, and chemotaxis.68 Of these, the most compelling evidence for a GPCR–ß-arrestin effect is the regulation of chemotaxis. T and B cells from ß-arrestin 2 knockout mice are strikingly impaired in their ability to migrate in response to CXCL12 in transwell and trans-endothelial migration assays.69 In addition, PAR-2 receptor–mediated cytoskeletal reorganization, polarized pseudopod extension, and chemotaxis are ERK1/2 dependent and inhibited by expression of a dominant-negative mutant of ß-arrestin 1,70 suggesting that the formation of ß-arrestin–ERK1/2 signaling complexes at the leading edge of a cell may direct localized actin assembly and drive chemotaxis. The mechanism for ß-arrestin–mediated chemotaxis is poorly defined, although a very recent article has suggested that cell shape change and membrane ruffling by Ang II and acetylcholine is facilitated by additional scaffolding with the actin-binding protein, Filamin A.71 The coincident observations that Ang II can modulate cell migration via ß-arrestin–dependent ERK1/2 activation,72 as well as neointimal hyperplasia and atherosclerotic lesion formation through G protein–dependent pathways, suggests that both G protein- and ß-arrestin–mediated signaling might contribute to the vascular injury response. The physiological relevance of this functional dichotomy has yet to be examined.

Finally, in vivo evidence is beginning to emerge suggesting that G protein–independent signaling by the AT1R may be involved in cardiovascular pathology. For example, a recent study of neural control of water and salt intake in response to AT1R stimulation demonstrated that G protein–independent ERK1/2 activation in the brain was sufficient to enhance salt but not water consumption in rats.73 The authors used an Ang II analogue Sar1Ile4Ile8-Ang II (SII-Ang II) that fails to activate the classical G{alpha}q-mediated second messengers, inositol phosphates, PKC and calcium, but still produces partial activation of ERK1/2.74 Numerous studies have established SII-Ang II as a ligand that signals via ß-arrestin–scaffolded MAPK.65,72,75 Indeed, it appears that MAPK is the only signaling pathway readily activated by this Ang II analogue. Using the complementary approach of cardiac-specific expression of a mutated Ang II receptor with impaired G protein coupling, it has been shown that mice expressing the uncoupled receptor developed more severe cardiac hypertrophy than mice expressing a comparable level of the wild-type AT1R.53 Interestingly, Src and cytoplasmic ERK1/2 activity was greater in mice expressing the mutated receptor, and the resultant hypertrophy was histologically distinct, with the mutant receptor producing greater hypertrophy and bradycardia, whereas the wild-type receptor generated more fibrosis and apoptosis. Although these experiments have yet be repeated in ß-arrestin 2 knockout mice, the data suggest that G protein–independent signals, possibly transmitted via ß-arrestins, and G protein–mediated signals independently contribute to the development of cardiac hypertrophy and failure.

Summary
Several discoveries over the past decade have demonstrated that the repertoire of GPCR signaling is far broader than originally envisioned (Figure). In addition to signals transmitted by G protein-regulated effectors, it is now clear that through mechanisms such as ErbB transactivation, GPCRs engage in extensive cross talk with other receptors and that these signals contribute to the proliferative and apoptotic effects of GPCR activation in vivo. Indeed, targeting this "final common pathway" of growth regulation may have clinical applications. It is also clear that GPCR desensitization, once viewed only as a mechanism of signal termination, is itself a means of conferring unique signaling properties on the receptor. PKA-dependent switching of ß2-adrenergic receptor coupling allows it to activate Gi-dependent signaling pathways that may ameliorate the deleterious effects of ß2-receptor activation in heart failure. ß-Arrestins, by acting as signaling scaffolds, confer unique enzymatic activity on GPCRs at the same time as they uncouple them from G proteins and may transmit G protein–independent signals that regulate VSMC migration and cardiomyocyte hypertrophy. Most significantly, these discoveries underscore the fact that GPCRs have >1 signaling mode and that in at least some cases, for example SII-Ang II, pharmacological agents can be developed that selectively activate or block only a subset of the full GPCR response profile. Although extensive additional work will be required to determine how these novel mechanisms of GPCR signaling contribute to human cardiovascular pathology, a deeper understanding of their role should permit us to design drugs that modify only the deleterious aspects of signaling or that target critical points of signal convergence.


Figure 1
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  		Receptor activation and desensitization both transmit GPCR signals. A, Ligand (H) binding to a GPCR catalyzes heterotrimeric G protein activation and a "first wave" of signal transduction. Depending on cell type, responses may include activation of the Raf-MEK1/2-ERK1/2 cascade via G protein–dependent pathways involving Gq/11, phospholipase Cß, PKC, and c-Raf or Gs, adenylyl cyclase (AC), cAMP, PKA, the small G protein Rap1, and B-Raf. In addition, many receptors that couple to Gi or Gq/11 catalyze ADAM-dependent shedding of EGFR (ErbB) ligands such as HB-EGF. EGFR transactivation permits GPCRs to activate Ras-dependent signaling. B, GPCR desensitization switches the receptor into distinct signaling modes that generate a "second wave" of signaling. PKA phosphorylation of ß2 adrenergic receptors uncouples them from Gs, leading to heterologous desensitization. PKA phosphorylated ß2 receptors also couple more efficiently to Gi, which further dampens cAMP production, while allowing the receptor to stimulate Gi signaling pathways such as activation of the ERK1/2 cascade. GRK phosphorylation of most GPCRs promotes ß-arrestin (ß-Arr) binding, leading to homologous desensitization and receptor sequestration. The receptor–arrestin complex functions as a "signalsome nucleus that initiates a number of G protein–independent signaling events. For receptors that form stable complexes with ß-arrestin, these include activation of a spatially constrained pool of ERK1/2. The ERK1/2 activation mechanism determines both the time course and distribution of ERK1/2 activity, causing the kinase to preferentially target extranuclear substrates or to translocate into the nucleus where it regulates transcription.


*    Acknowledgments
 
Sources of Funding

N.J.S. is supported by an Australian Postgraduate Award from the Government of Australia. L.M.L. is supported by National Institutes of Health grants DK55524, DK58283, and DK64353 and the Department of Veterans Affairs.

Disclosures

None.

Received April 27, 2006; first decision May 12, 2006; accepted June 7, 2006.


*    References
up arrowTop
 up arrowIntroduction
 up arrowG Protein Switching: Why...
 up arrowTransactivation of EGF...
 up arrowNovel G Protein-Independent...
 *References
 

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