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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Trends Mol Med. Author manuscript; available in PMC 2013 April 17.
Published in final edited form as:
PMCID: PMC3628754
NIHMSID: NIHMS453896

Therapeutic potential of β-arrestin- and G protein-biased agonists

Abstract

Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that β-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and β-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states.

Signaling by seven transmembrane receptors (7TMRs)

7TMRs represent the largest single family of cell surface receptors [1]. Members of this receptor superfamily are uniquely expressed throughout the body and are activated by a diverse host of ligands, including biogenic amines, hormones, peptides, proteins, growth factors, lipids, nucleic acids, odorants, tastants, protons (H+), ions (Ca2+) and light (photons) [1]. There are also several 7TMRs for which no clear ligand has yet been identified, the so-called orphan receptors [2]. The combination of ligand diversity and unique tissue expression makes 7TMRs attractive drug targets, with approximately 40% of modern drug therapy targeting 7TMRs, either directly or indirectly [3]. These include blockbusters such as opiates, antihistamines, α- and β-blockers, β-agonists, dopamine receptor blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors and selective serotonin reuptake inhibitors.

Drugs that directly target a 7TMR have been classically described as either agonists or antagonists for G protein signaling. The binding of an agonist to a 7TMR promotes a conformational change that results in the activation of receptor-associated heterotrimeric G proteins and consequent downstream signaling (Figure 1a). In addition to G protein activation, agonist binding promotes a process known as desensitization, which involves rapid phosphorylation of the receptor at the C terminus and intracellular loops, in large part by the G protein-coupled receptor kinases (GRKs). This combination of conformational change and phosphorylation dramatically increases the affinity of the receptor for a small family of multifunctional 7TMR regulatory or adaptor proteins known as the β-arrestins (β-arrestin1 and β-arrestin2). This association blocks subsequent G protein activation and plays an almost universal role in facilitating traditional 7TMR desensitization (Figure 1b). This process is complemented by the association of β-arrestins with second-messenger-metabolizing or -converting enzymes and components of the internalization machinery, which target the degradation of G protein-mediated signals and facilitate the removal of receptors from the cell surface (Figure 1c).

Figure 1
7TMR signaling and regulation by the GRKs and β-arrestins. (a) Agonist-stimulated, 7TMR-mediated G protein activation. (b) Subsequent desensitization of 7TMR-mediated G protein signaling and activation of β-arrestin-mediated signals. ( ...

Classically, agonists have been described as having linear efficacy [4], in which activation of the multiple signaling pathways downstream of a receptor (e.g. G protein signaling, receptor phosphorylation, β-arrestin recruitment and internalization) correlates with the degree of agonist-mediated receptor activation from partial to full (Figure 2a). In this scheme, antagonists have been described almost exclusively by their ability to block agonist-stimulated G protein activation. This view, in which agonists and antagonists can be defined purely in the context of a single form of signaling (most commonly G protein-mediated signaling), has guided the vast majority of modern 7TMR-based drug discovery (Figure 2a,b).

Figure 2
Differential 7TMR-stimulated G protein- and β-arrestin-mediated signaling. (a) Traditional agonist with linear efficacy. (b) Traditional antagonist, blocking all aspects of 7TMR signaling. (c) G protein-biased ligand, promoting 7TMR G protein ...

However, it has recently been appreciated that in addition to regulating receptor-stimulated G protein signaling, the β-arrestins are also capable of initiating distinct signals in their own right (Figure 1b). These signals are often both spatially and temporally distinct, and result in unique cellular and physiological or pathophysiological consequences (see [57] for a detailed review of β-arrestin signaling). With the discovery of β-arrestin-mediated signaling has come a new appreciation of biased agonism [4,810]. Biased agonism is best understood in a model in which different 7TMR active conformations are either competent for the full range of receptor activities or only for a restricted subset of them. Whereas balanced ligands stabilize the conformations that are competent for signaling to all downstream pathways, biased ligands stabilize only those conformations that are capable of promoting a subset of signaling effects [4,810]. For example, ligands can show bias for either G protein- (G protein-biased) or β-arrestin-mediated (β-arrestin-biased) signaling (Figure 2c,d). Such bias clearly adds a layer of texture [11] to the definition of ligand action. Using this framework, we could hypothesize that such ligands could more selectively target beneficial signaling and even block or negate detrimental or unwanted actions of receptor activation (e.g. side effects, toxicity or tolerance). Indeed, over the last decade a diversity of biased ligands for 7TMRs have been identified that selectively activate G proteins or β-arrestins (Table 1), and several of these seem to have distinct functional consequences when compared to traditional ligands with more linear efficacy [9]. Realization of the complexity of 7TMR signaling impacts both the way we describe 7TMR functions and how we apply these definitions to future 7TMR-based discovery and drug therapy.

Table 1
7TMR ligands showing β-arrestin or G protein bias. For effects that are merely consistent with bias, ligands are in italics

As described above, the β-arrestins are involved in multiple aspects of 7TMR-mediated signaling and regulation, and ligand bias has been described for numerous receptor subtypes (Table 1). Moreover, the β-arrestins have been implicated in numerous aspects of physiology and the pathophysiology of disease [6,7]. In the following sections, we highlight several examples for which targeting of selected β-arrestin-mediated activities might have or actually has therapeutic benefit (Table 2). Although these different activities might be linked functionally, for the purposes of discussion we broadly split the different roles of β-arrestin into desensitization of G protein signaling, receptor internalization or trafficking, and β-arrestin-mediated signaling.

Table 2
Physiology and pathophysiology of β-arrestin-mediated processes

G protein signaling and desensitization

Treatment with 7TMR agonists can be limited by the development of tachyphylaxis, a decrease in responsiveness to a drug with repeated dosing, and tolerance, whereby a higher drug dose is required with repeated doses to obtain the same effect. Both processes, which limit the utility of therapeutics, are largely thought to be regulated by β-arrestin-dependent receptor desensitization and downregulation. The design of G protein-biased ligands, which avoid β-arrestin activation and the associated negative consequences, represents a novel strategy for the development of improved agonist therapies with more sustained efficacy.

The β1 adrenergic receptor in heart failure

The β-arrestins are involved in a variety of cardiovascular processes, with a significant body of work focused on the prototypic β-adrenergic receptors (β-ARs). Some of the earliest work in this area involved β-arrestin1 knockout (KO) mice, which were more sensitive to the cardiac stimulatory effects of β-agonist when compared to wild-type (WT) mice, which strongly suggests the involvement of β-arrestin1 in cardiac β-AR desensitization [12]. Clinically, the β-agonist dobutamine is often used to provide inotropic support in patients with severe heart failure, but is associated with the development of tachyphylaxis. A G protein-biased ligand that limits β-arrestin-mediated desensitization and downregulation could provide a more consistent and efficacious therapeutic option.

The β2 adrenergic receptor in obstructive lung disease

In the pulmonary system, the β2-AR plays a major role in regulating airway smooth-muscle-cell contraction and bronchial tone. One major problem in the treatment of asthma is tachyphylaxis to β-agonist-stimulated bronchodilation, whereby repeated doses of either short- or long-acting agonists result in decreased bronchodilation [13]. This decreased responsiveness can lead patients to increase their use of β-agonists, thus increasing the health risks associated with elevated sympathetic activation and decreasing the effectiveness of rescue inhaler use during an asthma attack, and increasing the risk of death from such attacks [14]. β2-AR tachyphylaxis is also thought to result from increased receptor desensitization and down-regulation after agonist stimulation, an effect thought to be mediated by β-arrestins. β-Arrestin2 regulates receptor desensitization by sterically preventing the interaction between the receptor and G protein [15], by internalizing receptor [16], and by actively recruiting phosphodiesterases to degrade the cAMP generated by G protein signaling [17]. Studies have shown that the airway relaxation stimulated by the β-agonist albuterol is augmented in β-arrestin2 KO mice compared to WT controls [18]. Moreover, comparable results were obtained in transgenic mice expressing a mutant β2-AR deficient in GRK phosphorylation sites; thus, this mutant β2-AR is probably resistant to β-arrestin-mediated regulation [19]. These data therefore predict that a G protein-biased ligand that does not promote β-arrestin recruitment would result in less tachyphylaxis and would be a more effective therapeutic agent.

The µ opioid receptor (OR) and analgesia

The influence of β-arrestins on opioid analgesia and tolerance has been the subject of several studies [2022]. β-Arrestin2 KO mice experienced enhanced and prolonged morphine-induced analgesia [22] (effects not observed in β-arrestin1 KO mice [20]), as well as increased hypothermic responses compared to WT mice [22]. The β-arrestin2 KO mice also showed greater and more efficient central OR G protein coupling [22]. Interestingly, in addition to morphine, heroin also produced augmented analgesic efficacy in the β-arrestin2 KO mice; however, other µ-OR agonists, including etorphine, fentanyl and methadone, did not [20]. Together, these studies show that the analgesic efficacy of µ-OR agonists can be differentially regulated by β-arrestin2 in vivo. Consistent with these findings, β-arrestin2 KO mice were also resistant to the development of chronic morphine-induced tolerance, which correlated with preserved central OR G protein coupling [21]. Subsequent studies showed comparable results when β-arrestin2 was knocked down in vivo with either antisense [23] or small interfering (si)-RNA [24]. Conversely, adenoviral overexpression of β-arrestin2 in the brain attenuated morphine analgesia as evaluated by measuring response latencies in the hot-plate test [25]. These findings clearly show that β-arrestin2 is involved in regulating both morphine-stimulated OR desensitization and tolerance in vivo, and strongly suggest that a G protein-biased ligand produces enhanced and prolonged morphine-induced analgesia with reduced tolerance.

β-Arrestins and 7TMR internalization and trafficking

It has long been known that β-arrestins regulate the internalization and trafficking of 7TMRs through a variety of mechanisms. β-Arrestins interact with AP-2, an adapter protein for clathrin, thereby regulating receptor endocytosis into clathrin-coated pits [26,27]. Ubiquitination of β-arrestins regulates 7TMR trafficking: transient β-arrestin ubiquitination results in rapid recycling of the receptor, whereas stably ubiquinated β-arrestin targets the receptor to endosomes [28,29]. More broadly, β-arrestins act as adapters for several E3 ligases that catalyze ubiquitination, such as MDM2 [30], which ubiquitinates β-arrestin2; and other ligases such as NEDD4 [31] and AIP4 [32], which ubiquitinate 7TMRs and regulate their downregulation. The β-arrestins also interact with deubiquitinating enzymes such as the ubiquitin specific protease USP33 [29,33], thus providing a mechanism for the regulation of the β-arrestin–7TMR interaction [33]. Not surprisingly, there are several examples of disease states associated with alterations in receptor trafficking that might benefit from therapies that modulate β-arrestin-mediated functions.

The V2 vasopressin receptor in kidney function

Over 150 mutations of the V2 vasopressin receptor (V2R) have been identified that result in congenital nephrogenic diabetes insipidus (cNDI), a condition in which the kidney is unable to properly reabsorb water because the V2R does not respond appropriately to vasopressin [34]. Most of these mutations result in intracellular retention of a misfolded V2R, which limits its expression on the cell membrane and therefore the cell response to vasopressin. Mutation of one of the critical residues in the highly conserved DRY motif, R137H, results in a receptor that constitutively associates with β-arrestins in intracellular vesicles even in the absence of agonist [34], and is associated with constitutive receptor desensitization [35]. Thismutant receptor can be rescued by a cell-permeable V2R antagonist that acts as a pharmacological chaperone and restores the ability of the receptor to fold [36]. However, the constitutive β-arrestin association of R137H is not affected by this chaperone, even though patients with this mutation showed a clinical response to this therapy. Surprisingly, chaperones that are capable of rescuing other V2R mutants restore cAMP signaling in the absence of β-arrestin recruitment or receptor internalization, which suggests a role for G protein-biased agonists in the treatment of cNDI [37].

Conversely, the nephrogenic syndrome of inappropriate antidiuresis, a disorder associated with inappropriate retention of water, results from constitutive activity of the V2R [38]. It is caused by specific mutations of the V2R at R137 (R137C and R137L), the same residue that is mutated in cNDI [38]. Both R137C and R137L V2R mutants interact with β-arrestins in an agonist-independent manner but traffic considerably more efficiently to the plasma membrane than R137H [38], which suggests that receptor expression at the membrane is required for receptor function. As with cNDI, these findings suggest that ligands that restore V2R trafficking might have therapeutic utility in the treatment of the nephrogenic syndrome of inappropriate antidiuresis.

CXCR4 in autoimmune disease

A cytoplasmic tail truncation mutation in the chemokine receptor CXCR4 is found in the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, and leukocytes from patients with this disease display defective CXCR4 desensitization and enhanced chemotaxis [39]. The agonist-induced receptor internalization of CXCR4 is regulated specifically by GRK3 and β-arrestin2 and is defective in WHIM syndrome, whereas the chemotaxis of WHIM mutant leukocytes requires β-arrestin2 signaling, which suggests that the truncated receptor is capable of regulating β-arrestin-mediated signaling but not β-arrestin-mediated internalization or endocytosis [39].

CCR5 in HIV

HIV requires cell-surface coreceptors, either the CCR5 or CXCR4 chemokine receptor, to attach and gain entry to target cells. CCR5-tropic viruses are the predominant species in the early stages of infection, and patients with a homozygous truncation mutation of CCR5 (CCR5-Δ32) are resistant to HIV [40]. Accordingly there has been significant interest in targeting this receptor in the treatment of HIV infection [41]. A modified CCR5 ligand, aminooxypentane-RANTES (AOP-RANTES), promotes receptor internalization similar to endogenous RANTES, but unlike RANTES, AOP-RANTES does not allow the internalized CCR5 to recycle [42,43]. More highly potent derivatives of AOP-RANTES seem to be effective in preventing HIV infection of peripheral blood mononuclear cells [44]. The β-arrestins regulate this CCR5 trafficking, recycling and degradation [45], and these ligands probably regulate CCR5 trafficking via changes in β-arrestin activity. Thus, use of a ligand that modifies β-arrestin-regulated CCR5 trafficking might represent an attractive therapy in the treatment of HIV.

β-Arrestin-mediated signaling

It has now been over a decade since the first reports of β-arrestin-mediated signaling were published [4648]. β-Arrestin-mediated signaling encompasses a diverse range of pathways [5,4951], including kinase activation, transcriptional regulation and receptor transactivation. The best-characterized of these responses is the regulation of protein kinases, such as members of the mitogen-activated protein (MAP) and Src kinase families [5]. The list of physiologic responses that are regulated by β-arrestins continues to grow (Table 2), and drugs that selectively target β-arrestin-mediated signaling are currently being developed as therapeutic agents.

The β1-AR in heart failure

Recent studies have shown that cardiac β1-ARs can stimulate β-arrestin1- and -2-dependent signaling in the heart that results in transactivation of the epidermal growth factor receptor (EGFR), which is cardioprotective [52]. In addition, it is thought that chronic β-AR activation is cardiotoxic [5355] and that this in large part involves Gs signaling [55,56]. These combined observations suggest that a β-arrestin-biased ligand acting as a classical antagonist of cardiotoxic G protein signaling, while engaging cardioprotective β-arrestin signaling, could be therapeutically beneficial. Moreover, β-arrestin-biased ligands for both the β1-AR [57] and β2-AR [58,59] have recently been identified, with the β-blocker carvedilol a β-arrestin-biased ligand of both receptor subtypes [57,58]. Whether β-arrestin-mediated signaling plays a role in the cardioprotection associated with such compounds remains to be determined.

The angiotensin II type 1A receptor (AT1R) in cardiovascular disease

In addition to the β-ARs, AT1R-stimulated β-arrestin signaling has been the subject of several cardiovascular studies. In the heart and in isolated cardiomyocytes, AT1R-stimulated β-arrestin-dependent andGprotein-independent signaling promotes growth and hypertrophy [60], myocyte proliferation [61,62] and increased myocyte contractility [63,64]. Moreover, the newly identified β-arrestin-biased ligand Sar1,D-Ala8 angiotensin II (TRV120027) reduces mean arterial pressure, increases cardiac performance and preserves stroke volume in the anesthetized rat, whereas unbiased antagonists reduce cardiac performance [64]. In vascular smooth muscle cells, β-arrestin signaling increases protein synthesis [65] and is antiapoptotic [66]. Furthermore, cardiovascular function is in large part influenced by changes in body fluid homeostasis and salt balance, and AT1R-stimulated β-arrestin-associated signaling is involved in several related processes. For example, AT1R-stimulated β-arrestin1 signaling promotes adrenocortical aldosterone secretion both in vitro (cultured human adrenocortical carcinomacells, H295) and in vivo (adrenal-targeted adenoviral βarr1 overexpression in rats) [67]. Furthermore, central AT1R activation is associated with increased thirst and salt appetite [68]. Interestingly, the β-arrestin-biased AT1R ligand Sar1,Ile4,Ile8 angiotensin II (SII) [69] when injected directly into the brain stimulates central MAP kinase activation and salt intake, while blocking G protein-associated increases in central inositol triphosphate production and water intake [70]. Thus, AT1R-stimulated salt appetite would seem to be a β-arrestin-dependent process, at least in part. Overall, it seems that AT1R can stimulate a variety of β-arrestin-mediated cellular signals and associated processes involved in the maintenance of cardiovascular homeostasis.

GPR109A and the regulation of lipid homeostasis

A unique role for β-arrestin1-mediated signaling has recently been identified that involves the niacin receptor, GPR109A. Niacin is one of the most effective therapies for increasing HDL-cholesterol and decreasing triglycerides in the treatment of dyslipidemia [71,72]. However, the therapeutic utility of niacin is limited by the rather unpleasant side effect of cutaneous flushing, which significantly reduces patient compliance [71,72]. Recent studies have shown that the niacin-induced flushing response is dramatically reduced in β-arrestin1 KO mice, whereas the beneficial lipolytic effects remain intact [73]. This supports the hypothesis that a G protein-biased ligand would maintain beneficial effects on plasma lipids in the absence of β-arrestin-mediated flushing. Interestingly, GPR109A agonists have been identified that exhibit antilipolytic actions with significantly reduced cutaneous flushing [7478]. Some of these compounds also show reduced receptor internalization and extracellular signal-regulated kinase (ERK) activation [74], which could result from non-engagement of β-arrestin.

The parathyroid hormone receptor and bone mineral homeostasis

Bone mineral homeostasis requires a complex process of renewal involving a continuous cycle of bone formation and resorption. The parathyroid hormone (PTH) receptor plays an important role in regulating these processes, with recombinant human PTH 1–34 (Forteo®) currently approved for the treatment of osteoporosis. Previous studies have shown that β-arrestin2 plays a role in regulating PTH-receptor-mediated signaling [7984], with effects on bone formation and resorption [85,86], as well as related gene expression [87,88]. Furthermore, studies have shown that the PTH receptor can stimulate both G protein- and β-arrestin-mediated signals, and that these signals can be selectively engaged by both G protein- and β-arrestin-biased ligands [89,90]. Most recently, it has been shown that the β-arrestin-biased ligand (D-Trp12,Tyr34)-PTH(7–34), which simultaneously stimulates receptor-mediated β-arrestin signaling and blocks G protein signaling, promotes anabolic bone formation in the absence of bone resorption, and that this activity is abolished in β-arrestin2 KO mice [91]. These studies have thus identified a novel β-arrestin-mediated pathway and a unique β-arrestin-biased ligand that positively affects anabolic bone formation. Targeting of this newly identified mechanism of action could represent a novel therapeutic strategy for the treatment of osteoporosis.

Opioid side effects

Opioid therapy is associated with several adverse side effects, including respiratory suppression, constipation, and the development of tolerance and physical dependence. β-Arrestin2 is responsible for desensitization of the receptor after chronic morphine treatment, and β-arrestin2 KO mice are protected from the development of tolerance, the requirement for increasing doses of opioids to maintain the same antinociceptive effect [21]. Studies have shown that β-arrestin2 KO mice are also resistant to morphine-induced respiratory suppression when compared to WT mice [92]. In addition, β-arrestin2 KO mice were less sensitive to some of the adverse gastrointestinal effects of µ-OR agonists. Specifically, β-arrestin2 KO mice were resistant to the effects of morphine on fecal boli accumulation and to a lesser extent colonic propulsion when compared to WT mice [92,93]. The β-arrestin2 KO mice were not, however, resistant to the inhibitory effects of morphine on small intestinal transit. Interestingly, the peripherally restricted µ-OR agonist and antidiarrheal agent loperamide significantly reduced colonic propulsion in WT mice, and these effects were completely abolished in β-arrestin2 KO mice [92]. This suggests that peripherally restricted β-arrestin-biased agonists might be useful in the treatment of diarrhea and other hypermotility disorders.

Cancer cell metastasis and cell motility

The β-arrestins are involved in several cancer-related signals and processes via a range of receptor subtypes. Moreover, elevated β-arrestin mRNA levels have been observed in cancerous tumors and tumorigenic cancer cell lines [94]. Of note, β-arrestin1 plays a role in nicotine-induced proliferation of non-small-cell lung cancer cells via a process involving a β-arrestin1-scaffolded complex of the nicotinic acetylcholine receptor and Src, as well as downstream signaling via the MAP kinase and Rb-Raf-1 pathways [95]. Prostaglandin-E2-stimulated EP2- and EP4-receptor-mediated transactivation of EGFR also involves a complex of receptor, β-arrestin1 and Src, which is involved in mouse skin papilloma development [96] and colorectal carcinoma cell migration and metastasis [97], respectively. Similarly, in ovarian cancer cells the β-arrestins mediate endothelin type A (ETA)-receptor-stimulated EGFR transactivation via Src, as well as effects on β-catenin, which are thought to be involved in both cell invasion and metastasis [98,99]. Lysophosphatidic acid (LPA) receptor activation is associated with enhanced breast cancer cell metastasis [94], and siRNA-mediated knockdown of either β-arrestin 1 or 2 in breast cancer cells reduces LPA-stimulated transwell migration and 3D Matrigel invasion [94]. Conversely, transgenic overexpression of β-arrestin1 in mice promotes tumor angiogenesis and progression [100].

In addition to activating proliferative signaling pathways, β-arrestins are also involved in several pathways that suppress tumor growth and metastasis. For example, transforming growth factor (TGF)-β inhibits epithelial and cancer cell migration via β-arrestin2-mediated activation of cell division cycle (CDC)-42 [101]. β-Arrestin2 KO mice also have increased tumor growth and metastasis mediated by host changes in inflammation and angiogenesis in a heterotopic model of lung cancer in which both WT and β-arrestin2 KO mice were injected with cells derived from a spontaneously occurring lung cancer tumor in C57BL/6 mice [102]. In androgen-dependent prostate cancer cells, β-arrestin2 acts as an androgen receptor corepressor and promotes the association of MDM2 with the receptor and its consequent ubiquitylation and degradation [103]. The above studies clearly demonstrate that the β-arrestins play roles in a variety of pro- and anticancer-related signals and processes in both neoplastic cells and the surrounding host environment via several different receptor subtypes. The diversity of this influence might provide insight into potential targets for future chemotherapeutic strategies.

Emerging areas of interest

In addition to the specific examples highlighting β-arrestin-mediated functions (Table 2), several reports describe processes that are probably β-arrestin-mediated. One recent example, which might have broad therapeutic implications in the treatment of cognitive disorders, involves the M3 muscarinic receptor. Specifically, M3-receptor-dependent learning and memory require processes that depend on receptor phosphorylation, consistent with β-arrestin recruitment and apparently independent of G protein signaling [104]. These data suggest that a β-arrestin-biased ligand at the M3 receptor might promote both learning and memory, and might thus be beneficial in the treatment of cognitive disorders such as Alzheimer’s disease. The exact role of β-arrestin in such processes and the therapeutic potential of targeting β-arrestin-mediated signaling will require further study.

Concluding remarks

The β-arrestins are intimately involved in numerous aspects of 7TMR signaling and regulation, and accordingly influence manifold physiological and pathophysiological processes. β-Arrestin-mediated signaling is a relatively new area of 7TMR research, especially when compared to the study of more traditional G protein signals, and continued efforts in this area will undoubtedly lead to the discovery of additional roles for β-arrestins in 7TMR biology. Of particular interest, the ability of biased ligands to differentiate between β-arrestin and G protein functions at the receptor level should facilitate selective engagement of a subset of signals from a particular 7TMR. In most instances, identification of biased ligands for a specific 7TMR target is rather straightforward. The major bottleneck in determining the therapeutic potential of G protein- and β-arrestin-biased agonists is the lack of knowledge regarding the roles of these distinct signaling pathways in both health and disease. Therefore, studies should focus on the development and use of biased agonists as tool compounds in cellular and animal models of disease to more clearly delineate the physiologic consequences of these two signaling mechanisms. We expect that clearer definitions of the role of β-arrestins and G proteins in 7TMR signaling will facilitate the development of improved therapeutic agents that target 7TMRs (and potentially β-arrestin- and G protein-mediated signals directly) with improved efficacy and fewer side effects.

Glossary

Antinociceptive effect
effect that leads to a decreased sensation of pain
Congenital nephrogenic diabetes insipidus (cNDI)
condition in which the kidney is unable to properly reabsorb water because it does not respond appropriately to vasopressin
Inotropic support
therapy aimed at improving the contractile function of the heart
Nephrogenic syndrome of inappropriate antidiuresis
disorder in which the body inappropriately retains water due to a defect in signaling in the kidney
Tachyphylaxis
decrease in responsiveness to a drug with repeated dosing
Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome
congenital immunodeficiency due to mutation of CXCR4 that results in neutropenia

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