G Protein-Coupled Receptor with the Aging-Related Mechanisms: Comparison
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Please note this is a comparison between Version 3 by Camila Xu and Version 2 by Stuart Russell Maudsley.

G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological, and also pathophysiological, process. G protein-coupled receptor 19 (GPR19), is a novel orphan GPCR that likely represents an important new target for novel remedial strategies for pathological disease conditions associated with aging-related cellular and tissue damage.

  • GPR19
  • GPCR
  • aging
  • therapeutics
  • longevity

1. Introduction

GPCRs constitute one of the most diverse groups of transmembrane signal transducers that control a panoply of physiological processes in many species, ranging from C. elegans to Homo sapiens. The GPCR transmembrane superfamily is characterized by a common seven α-helical transmembrane domain motifs. GPCRs represent one of the most therapeutically important molecular targets in clinical medicine [1,2,3,4][1][2][3][4]. GPCRs facilitate communication between cells in tissues across long distances in the body, thereby enabling the capacity for systems-level therapeutic actions [5,6,7,8][5][6][7][8]. In addition to this long-distance signal transduction role, GPCRs also regulate intracellular signal transduction scenarios that regulate cellular stress responses [9]. Underlining their importance to therapeutic development, medicines have been historically developed to exploit these GPCR systems for many years, even before the discovery of GPCRs themselves [10]. OurThis research, as well as others, have begun to demonstrate that the GPCR systems can be targeted to control multiple physiological systems across the body and thus present an ability for GPCR ligands to control complex disorders such as pathological aging [2,5][2][5]. Implicit in this systems-wide functionality is the connected concept that GPCR activity is both vital for long-range tissue-to-tissue communication [5] and also the creation of stress-sensitive GPCR signaling networks at the single cellular level [9]. In this regard, wresearchers will highlight the Class A orphan GPCR, G protein-coupled receptor 19 (GPR19), as a potential novel regulator in the metabolic aging process.

2. GPCR Signaling

Given the importance of GPCR signaling in controlling physiological functions, multiple investigations over several decades have sought to fully appreciate how these transmembrane receptors control cellular activity at the signal transduction level. From a functional receptor pharmacological approach, controllers of these receptors were originally designed to exert either a simple positive effect (increasing the activity of downstream signaling systems, e.g., adenylate cyclase) or by inhibiting this activity by occupying the receptor and antagonizing the positive actions of stimulatory ligands. Therapeutic agents were classified as simple agonists (stimulatory) or antagonists (inhibitory) based on the concept that receptors could exist predominantly in two distinct states, i.e., inactive and active. Over the next thirty years, intense research largely confirmed this ‘two-state’ GPCR model [11,12,13,14,15,16,17][11][12][13][14][15][16][17]. Using specific site-directed mutagenesis of key residues in GPCRs [18], it was demonstrated that GPCRs indeed likely exist in a spontaneous equilibrium between two conformations, i.e., active (R*) and inactive (R). The active conformation is naturally stabilized by agonist binding or, in these numerous experiments, by residue mutation that serves to relax intramolecular constraints [18,19,20,21,22,23][18][19][20][21][22][23]. In this initial functional model, GPCRs transmit signals through their capacity to act as guanine nucleotide exchange factors for heterotrimeric guanine nucleotide-binding proteins (G proteins) in response to stimulatory ligand binding (or via constitutively activating point mutagenesis). Ligand-mediated G protein activation is initiated through conformational rearrangement of the heptahelical GPCR core and juxtamembrane loop regions, eventually catalyzing the exchange of GDP for GTP on the receptor-associated Gα subunit [24,25,26,27,28][24][25][26][27][28]. Guanine nucleotide exchange (GDP for GTP) then initiates the dissociation of the heterotrimeric G protein from the GPCR, followed by the dissociation of the G protein heterotrimer releasing free GTP-bound α and βγ subcomplexes. These two signaling components can stimulate, inhibit or physically recruit multiple downstream signal transduction effectors, e.g., adenylyl cyclase (AC), phospholipase C (PLC), GPCR kinases (GRKs) or GRK-interacting proteins [29]. In this manner, the heterotrimeric G protein can transmit information to the intracellular milieu about the qualitative and quantitative nature of specific extracellular stimuli [30,31][30][31]. There are 16 Gα, 5 Gβ and 13 Gγ subunits in humans, which allows many different aggregations and signaling outputs [32]. The responses range from activation to inhibition, and G proteins are classified based on the downstream function of the alpha (α) subunit into four families, Gαs, Gαi/o, Gαq/11, and Gα12/13. Gαs activates adenylyl cyclase, which then converts ATP into the second messenger cyclic adenosine monophosphate (cAMP) and activates the cAMP-dependent pathway. Conversely, Gαi/o decreases cAMP levels [33]. Apart from the classical G protein signaling, multiple lines of research have validated the existence of multiple non-G protein signaling activities, such as β-arrestin [34[34][35][36],35,36], proto-oncogene tyrosine-protein kinase Src (c-Src) [37,38,39][37][38][39] and the ADP-ribosylation factor GTPase activating protein-2 (GIT2) [40,41,42][40][41][42]. Thus, it is now clear that GPCR signaling is more nuanced and complex than previously thought. The dogma of simple physiological G protein signaling specificity of downstream signaling was broken with the initial demonstration that alternative modes of signaling, e.g., the first being the β-arrestin paradigm, are physiologically relevant and are therapeutically tractable [28,34,35,36,43,44,45,46,47][28][34][35][36][43][44][45][46][47]. β-arrestins were first characterized as negative regulatory proteins for signaling through G proteins and were considered responsible for GPCR internalization and separation from G protein engagement [48,49,50][48][49][50]. β-arrestin has been subsequently shown to serve as a scaffold for a variety of signaling complexes associated with GPCR signaling pathways [28,34,43][28][34][43]. While the field of non-G protein-dependent GPCR signaling has been historically dominated by β-arrestin activity, several other modalities have been demonstrated, including Janus kinase 2 (JAK2) [51], 14-3-3 proteins [52], RGS proteins [53], Proline-rich tyrosine kinase 2 (PYK2) [39,54][39][54] and the ADP-ribosylation factor GTPase-activating protein 2 (GIT2) [40,55][40][55]. With regards to this last GPCR signaling adaptor, GIT2, several strong contrasts to β-arrestin signaling have been reported, thus making this paradigm an interesting one to compare with the pioneering β-arrestin pathway [2,9,29][2][9][29]. With the specific link to aging paradigms, it has been shown that β-arrestin activation leads to increased DNA damage in stress conditions, degradation of p53, suppression of NF-kB and the promotion of apoptosis [56,57][56][57]. Conversely, it appears that GIT2 may represent a natural mechanism to prevent aging-associated molecular and cellular damage. The GPCR-kinase interacting protein (GIT) family of proteins (GIT1 and GIT2) were originally identified as GRK and GPCR interacting proteins [58]. Subsequently, it has been shown that especially GIT2 exerts systemic effects upon a multitude of signaling and physiological systems, including oxidative stress resistance [59], glucose metabolism [60], circadian rhythm regulation [61], mitochondrial activity [41,60][41][60], DNA damage repair response [40[40][62],62], immunosenescence [61] and gender-specific lifespan regulation [41]. Given this information, it is unsurprising that additional interest in non-G protein-dominated GPCR signaling pathways has been shown with respect to the proposal that signaling paradigms such as β-arrestin and GIT2 may indeed possess specific benefits for the GPCR-mediated interdiction of aging-related disease [35,40,42,63,64,65,66,67][35][40][42][63][64][65][66][67]. For both signaling paradigms, significant evidence has shown that these two GPCR signaling modalities converge on the regulation of energy metabolism and DNA damage/repair [34,42,56,57,59,60,61,62,66,68,69,70,71,72,73,74,75][34][42][56][57][59][60][61][62][66][68][69][70][71][72][73][74][75].

3. Aging and GPCR Functionality

Aging and age-related damage of cellular proteins and nucleic acids are inevitable results of lifelong cellular metabolic activity [40,60,62,76,77,78][40][60][62][76][77][78]. This cellular damage occurs most frequently because of the production of deleterious metabolites, e.g., reactive oxygen species (ROS), as by-products of energy management processes such as mitochondrial oxidative phosphorylation [9,79,80,81][9][79][80][81]. There are many other sources of aging-related damage, but many lines of evidence have suggested that this process is one of the most potent sources of recurring cellular damage and, ultimately, age-related disease [82,83,84,85,86,87][82][83][84][85][86][87]. This stress-related damage essentially degrades the functionality of active signaling systems as well as reactive cytoprotective cellular systems that exist to combat the metabolically induced cellular damage [2,9,88,89,90,91][2][9][88][89][90][91]. In recent years it has been demonstrated that—as with many other forms of cellular and tissue signaling [90,92,93][90][92][93]—stress response and DNA damage repair processes are strongly controlled and regulated by signaling networks composed of multiple GPCR types [5,9,29,63,64,65,66,73,94,95][5][9][29][63][64][65][66][73][94][95]. Thus, well-informed therapeutic targeting of GPCRs holds a strong promise for the generation of a broad series of anti-aging therapeutics. GPCRs represent one of the most important therapeutic targets for controlling disease generation and progression [96,97][96][97]. Underlying their importance in the broad range of biological functions, GPCRs are the most structurally diverse family of transmembrane proteins. The superfamily comprises more than 800 proteins, which are grouped based on evolutionary homology and common physiological ligands. Human GPCRs are divided into six major classes, class A (rhodopsin-like), class B1 (secretin receptor-like), class B2 (adhesion receptors), class C (metabotropic glutamate receptor-like) and class F (frizzled-like) subfamilies, as well as the taste 2 sensory receptor subfamily [98]. GPCRs sense a tremendous variety of stimulating entities ranging from photons, ions, and neurotransmitters, to complex hormones and exogenous animal toxins. This nuanced sensory system allows cells to react quickly to diverse endogenous and environmental perturbations [99]. GPCRs are of major interest for drug development due to their regulatory function for a multitude of physiological processes, as well as their accessibility for exogenous ligands. Hauser et al. evaluated in 2017 that 475 FDA-approved drugs target GPCRs, which is 34% of all FDA-approved drugs [96].

4. GPCR-Based Control of Aging-Related Mechanisms

As wresearchers have previously described, it has been proposed that non-G protein-dependent signaling paradigms may hold specific promise for the amelioration of aging-associated diseases [2,29,42][2][29][42]. Arrestin-dependent signaling is one of the most important and well-characterized of these signaling modalities [34,94,100][34][94][100]. Recent translational research has demonstrated that the β-arrestin-based signaling modality can generate a clinically relevant signaling paradigm [36,46,47,101][36][46][47][101]. Using a novel, in vivo-biased signaling demonstration, it was found that β-arrestin-GPCR complexes likely possess the ability to elicit a coherently conserved signaling cascade across multiple tissues, distinct from the G protein paradigm, even after a month of continuous drug dosing of the biased agent [46]. Furthermore, and in stark contrast to G protein-sourced signaling that primarily controls acute intermediary cell metabolism events (e.g., intracellular calcium mobilization), β-arrestin-dependent signaling generates a strong transcriptional and translational signaling functionality [102,103,104,105][102][103][104][105]. This aspect of β-arrestin-dependent signaling, therefore, lends itself to the concept that β-arrestin-biased ligands could be rationally designed to therapeutically regulate complex protein networks that underpin many complex aging-related diseases, e.g., Type II Diabetes Mellitus (T2DM), neurodegeneration and cancer [29,91,106][29][91][106]. The expression levels and signaling activity of β-arrestin have been shown to be involved with metabolic aging conditions such as Alzheimer’s disease [107[107][108],108], Parkinson’s’ disease [109[109][110][111],110,111], T2DM [112,113,114][112][113][114], osteoporosis [44,46,115][44][46][115] and schizophrenia [116,117][116][117]. In a similar vein, research has also demonstrated that the GPCR adaptor GIT2 can play a pivotal role in metabolic aging conditions and disorders, including neurodegenerative diseases [118[118][119],119], T2DM [60] osteoporosis [120,121][120][121] and psycho-affective disorders [122,123][122][123]. In addition to these two major forms of GPCR signaling adaptors, considerable evidence has been generated to demonstrate the role of GRKs, PYK2 and JAK2 in aging-related conditions associated with metabolic dysfunction [2]. This consistent finding, therefore, suggests that perhaps the association of GPCRs with these non-G protein signal adaptors may create a stress-sensory mechanistic network of receptors that naturally control the severity of these conditions [9]. Hence, wresearchers contend that the molecular intersection between cellular damage control and metabolic dysfunction systems plays a pivotal role in regulating the balance of energy regulation and cellular stress responses. While presenting tremendous promise for the future of pharmacotherapy via precision medicine, the multiplicity and importance of β-arrestin and GIT2 in a plethora of physiological processes does raise the possibility of incurring systemic side effects resulting from excessive, or even total β-arrestin or GIT2 bias, at the expense of G protein activity. Hence, an intelligently informed and subtle approach to signaling bias exploitation should be taken. Potentially the development of novel biased ligands targeting the β-arrestin-or GIT2-associated receptorsome currently represents a vital new pharmacotherapeutic domain [40,44,63,124,125][40][44][63][124][125].

References

  1. Sriram, K.; Insel, P.A. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 2018, 93, 251–258.
  2. Van Gastel, J.; Leysen, H.; Boddaert, J.; Vangenechten, L.; Luttrell, L.M.; Martin, B.; Maudsley, S. Aging-related modifications to G protein-coupled receptor signaling diversity. Pharmacol. Ther. 2021, 223, 107793.
  3. Rask-Andersen, M.; Masuram, S.; Schiöth, H.B. The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 9–26.
  4. Santos, R.; Ursu, O.; Gaulton, A.; Bento, A.P.; Donadi, R.S.; Bologa, C.G.; Karlsson, A.; Al-Lazikani, B.; Hersey, A.; Oprea, T.I.; et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 2017, 16, 19–34.
  5. Janssens, J.; Etienne, H.; Idriss, S.; Azmi, A.; Martin, B.; Maudsley, S. Systems-Level G Protein-Coupled Receptor Therapy Across a Neurodegenerative Continuum by the GLP-1 Receptor System. Front. Endocrinol. 2014, 5, 142.
  6. Tse, L.H.; Wong, Y.H. GPCRs in Autocrine and Paracrine Regulations. Front. Endocrinol. 2019, 10, 428.
  7. De Oliveira, P.G.; Ramos, M.L.S.; Amaro, A.J.; Dias, R.A.; Vieira, S.I. G(i/o)-Protein Coupled Receptors in the Aging Brain. Front. Aging Neurosci. 2019, 11, 89.
  8. Husted, A.S.; Trauelsen, M.; Rudenko, O.; Hjorth, S.A.; Schwartz, T.W. GPCR-Mediated Signaling of Metabolites. Cell Metab. 2017, 25, 777–796.
  9. Leysen, H.; Walter, D.; Christiaenssen, B.; Vandoren, R.; Harputluoğlu, İ.; van Loon, N.; Maudsley, S. GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease. Int. J. Mol. Sci. 2021, 22, 13387.
  10. Del Castillo, J.; Katz, B. Interaction at end-plate receptors between different choline derivatives. Proc. R. Soc. Lond. B Biol. Sci. 1957, 146, 369–381.
  11. De Lean, A.; Stadel, J.M.; Lefkowitz, R.J. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J. Biol. Chem. 1980, 255, 7108–7117.
  12. Gardella, T.J.; Luck, M.D.; Jensen, G.S.; Schipani, E.; Potts, J.T., Jr.; Jüppner, H. Inverse agonism of amino-terminally truncated parathyroid hormone (PTH) and PTH-related peptide (PTHrP) analogs revealed with constitutively active mutant PTH/PTHrP receptors. Endocrinology 1996, 137, 3936–3941.
  13. Gether, U.; Lin, S.; Kobilka, B.K. Fluorescent labeling of purified beta 2 adrenergic receptor. Evidence for ligand-specific conformational changes. J. Biol. Chem. 1995, 270, 28268–28275.
  14. Leff, P. The two-state model of receptor activation. Trends Pharmacol. Sci. 1995, 16, 89–97.
  15. Parma, J.; Duprez, L.; van Sande, J.; Cochaux, P.; Gervy, C.; Mockel, J.; Dumont, J.; Vassart, G. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993, 365, 649–651.
  16. Pozvek, G.; Hilton, J.M.; Quiza, M.; Houssami, S.; Sexton, P.M. Structure/function relationships of calcitonin analogues as agonists, antagonists, or inverse agonists in a constitutively activated receptor cell system. Mol. Pharmacol. 1997, 51, 658–665.
  17. Shenker, A.; Laue, L.; Kosugi, S.; Merendino, J.J., Jr.; Minegishi, T.; Cutler, G.B., Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993, 365, 652–654.
  18. Samama, P.; Cotecchia, S.; Costa, T.; Lefkowitz, R.J. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J. Biol. Chem. 1993, 268, 4625–4636.
  19. Ceresa, B.P.; Limbird, L.E. Mutation of an aspartate residue highly conserved among G-protein-coupled receptors results in nonreciprocal disruption of alpha 2-adrenergic receptor-G-protein interactions. A negative charge at amino acid residue 79 forecasts alpha 2A-adrenergic receptor sensitivity to allosteric modulation by monovalent cations and fully effective receptor/G-protein coupling. J. Biol. Chem. 1994, 269, 29557–29564.
  20. Morin, D.; Cotte, N.; Balestre, M.N.; Mouillac, B.; Manning, M.; Breton, C.; Barberis, C. The D136A mutation of the V2 vasopressin receptor induces a constitutive activity which permits discrimination between antagonists with partial agonist and inverse agonist activities. FEBS Lett. 1998, 441, 470–475.
  21. Alewijnse, A.E.; Timmerman, H.; Jacobs, E.H.; Smit, M.J.; Roovers, E.; Cotecchia, S.; Leurs, R. The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H(2) receptor. Mol. Pharmacol. 2000, 57, 890–898.
  22. Pauwels, P.J.; Tardif, S.; Wurch, T.; Colpaert, F.C. Facilitation of constitutive alpha(2A)-adrenoceptor activity by both single amino acid mutation (Thr(373)Lys) and g(alphao) protein coexpression: Evidence for inverse agonism. J. Pharmacol. Exp. Ther. 2000, 292, 654–663.
  23. Maudsley, S.; Davidson, L.; Pawson, A.J.; Chan, R.; López de Maturana, R.; Millar, R.P. Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res. 2004, 64, 7533–7544.
  24. Conklin, B.R.; Bourne, H.R. Structural elements of G alpha subunits that interact with G beta gamma, receptors, and effectors. Cell 1993, 73, 631–641.
  25. Ernst, O.P.; Hofmann, K.P.; Sakmar, T.P. Characterization of rhodopsin mutants that bind transducin but fail to induce GTP nucleotide uptake. Classification of mutant pigments by fluorescence, nucleotide release, and flash-induced light-scattering assays. J. Biol. Chem. 1995, 270, 10580–10586.
  26. Farahbakhsh, Z.T.; Hideg, K.; Hubbell, W.L. Photoactivated conformational changes in rhodopsin: A time-resolved spin label study. Science 1993, 262, 1416–1419.
  27. Franke, R.R.; Sakmar, T.P.; Graham, R.M.; Khorana, H.G. Structure and function in rhodopsin. Studies of the interaction between the rhodopsin cytoplasmic domain and transducin. J. Biol. Chem. 1992, 267, 14767–14774.
  28. Donnelly, D.; Maudsley, S.; Gent, J.P.; Moser, R.N.; Hurrell, C.R.; Findlay, J.B. Conserved polar residues in the transmembrane domain of the human tachykinin NK2 receptor: Functional roles and structural implications. Biochem. J. 1999, 339 Pt 1, 55–61.
  29. Van Gastel, J.; Hendrickx, J.O.; Leysen, H.; Santos-Otte, P.; Luttrell, L.M.; Martin, B.; Maudsley, S. β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders. Front. Pharmacol. 2018, 9, 1369.
  30. Wess, J. G-protein-coupled receptors: Molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J. 1997, 11, 346–354.
  31. Hamm, H.E. The many faces of G protein signaling. J. Biol. Chem. 1998, 273, 669–672.
  32. Liu, Y.; Yang, Y.; Ward, R.; An, S.; Guo, X.X.; Li, W.; Xu, T.R. Biased signalling: The instinctive skill of the cell in the selection of appropriate signalling pathways. Biochem. J. 2015, 470, 155–167.
  33. Syrovatkina, V.; Alegre, K.O.; Dey, R.; Huang, X.Y. Regulation, Signaling, and Physiological Functions of G-Proteins. J. Mol. Biol. 2016, 428, 3850–3868.
  34. Luttrell, L.M.; Ferguson, S.S.G.; Daaka, Y.; Miller, W.E.; Maudsley, S.; Della Rocca, G.J.; Lin, F.T.; Kawakatsu, H.; Owada, K.; Luttrell, D.K.; et al. β-arrestin-dependent formation of β2 adrenergic receptor-src protein kinase complexes. Science 1999, 283, 655–661.
  35. Van Gastel, J.; Etienne, H.; Azmi, A.; Maudsley, S. The synergistic GIT2-RXFP3 system in the brain and its importance in age-related disorders. Front. Aging Neurosci. 2016, 3, 8.
  36. Maudsley, S.; Martin, B.; Janssens, J.; Etienne, H.; Jushaj, A.; van Gastel, J.; Willemsen, A.; Chen, H.; Gesty-Palmer, D.; Luttrell, L.M. Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation. Methods 2016, 92, 51–63.
  37. Chadwick, W.; Keselman, A.; Park, S.S.; Zhou, Y.; Wang, L.; Brenneman, R.; Martin, B.; Maudsley, S. Repetitive peroxide exposure reveals pleiotropic mitogen-activated protein kinase signaling mechanisms. J. Signal Transduct. 2011, 2011, 636951.
  38. Davidson, L.; Pawson, A.J.; López de Maturana, R.; Freestone, S.H.; Barran, P.; Millar, R.P.; Maudsley, S. Gonadotropin-releasing hormone-induced activation of diacylglycerol kinase-zeta and its association with active c-src. J. Biol. Chem. 2004, 279, 11906–11916.
  39. Maudsley, S.; Davidson, L.; Pawson, A.J.; Freestone, S.H.; López de Maturana, R.; Thomson, A.A.; Millar, R.P. Gonadotropin-releasing hormone functionally antagonizes testosterone activation of the human androgen receptor in prostate cells through focal adhesion complexes involving Hic-5. Neuroendocrinology 2006, 84, 285–300.
  40. Van Gastel, J.; Leysen, H.; Santos-Otte, P.; Hendrickx, J.O.; Azmi, A.; Martin, B.; Maudsley, S. The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage. Aging 2019, 11, 11268–11313.
  41. Van Gastel, J.; Cai, H.; Cong, W.N.; Chadwick, W.; Daimon, C.; Leysen, H.; Hendrickx, J.O.; de Schepper, R.; Vangenechten, L.; Van Turnhout, J.; et al. Multidimensional informatic deconvolution defines gender-specific roles of hypothalamic GIT2 in aging trajectories. Mech. Ageing Dev. 2019, 184, 111150.
  42. Van Gastel, J.; Boddaert, J.; Jushaj, A.; Premont, R.T.; Luttrell, L.M.; Janssens, J.; Martin, B.; Maudsley, S. GIT2-A keystone in ageing and age-related disease. Ageing Res. Rev. 2018, 43, 46–63.
  43. McDonald, P.H.; Chow, C.W.; Miller, W.E.; Laporte, S.A.; Field, M.E.; Lin, F.T.; Davis, R.J.; Lefkowitz, R.J. Beta-arrestin 2: A receptor-regulated MAPK scaffold for the activation of JNK3. Science 2000, 290, 1574–1577.
  44. Gesty-Palmer, D.; Yuan, L.; Martin, B.; Wood, W.H., III; Lee, M.H.; Janech, M.G.; Tsoi, L.C.; Zheng, W.J.; Luttrell, L.M.; Maudsley, S. β-arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo. Mol. Endocrinol. 2013, 27, 296–314.
  45. Maudsley, S.; Siddiqui, S.; Martin, B. Systems analysis of arrestin pathway functions. Prog. Mol. Biol. Transl. Sci. 2013, 118, 431–467.
  46. Maudsley, S.; Martin, B.; Gesty-Palmer, D.; Cheung, H.; Johnson, C.; Patel, S.; Becker, K.G.; Wood, W.H., III; Zhang, Y.; Lehrmann, E.; et al. Delineation of a conserved arrestin-biased signaling repertoire in vivo. Mol. Pharmacol. 2015, 87, 706–717.
  47. Luttrell, L.M.; Maudsley, S.; Bohn, L.M. Fulfilling the Promise of “Biased” G Protein-Coupled Receptor Agonism. Mol. Pharmacol. 2015, 88, 579–588.
  48. Wootten, D.; Christopoulos, A.; Marti-Solano, M.; Babu, M.M.; Sexton, P.M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 2018, 19, 638–653.
  49. Ferguson, S.S. Evolving concepts in G protein-coupled receptor endocytosis: The role in receptor desensitization and signaling. Pharmacol. Rev. 2001, 53, 1–24.
  50. Pierce, K.L.; Maudsley, S.; Daaka, Y.; Luttrell, L.M.; Lefkowitz, R.J. Role of endocytosis in the activation of the extracellular signal-regulated kinase cascade by sequestering and nonsequestering G protein-coupled receptors. Proc. Natl. Acad. Sci. USA 2000, 97, 1489–1494.
  51. Ferrand, A.; Kowalski-Chauvel, A.; Bertrand, C.; Escrieut, C.; Mathieu, A.; Portolan, G.; Pradayrol, L.; Fourmy, D.; Dufresne, M.; Seva, C. A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R: Implication of this signaling pathway in pancreatic tumor models. J. Biol. Chem. 2005, 280, 10710–10715.
  52. Li, H.; Eishingdrelo, A.; Kongsamut, S.; Eishingdrelo, H. G-protein-coupled receptors mediate 14-3-3 signal transduction. Signal Transduct. Target. Ther. 2016, 1, 16018.
  53. Jeanneteau, F.; Guillin, O.; Diaz, J.; Griffon, N.; Sokoloff, P. GIPC recruits GAIP (RGS19) to attenuate dopamine D2 receptor signaling. Mol. Biol. Cell 2004, 15, 4926–4937.
  54. Andreev, J.; Galisteo, M.L.; Kranenburg, O.; Logan, S.K.; Chiu, E.S.; Okigaki, M.; Cary, L.A.; Moolenaar, W.H.; Schlessinger, J. Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem. 2001, 276, 20130–20135.
  55. Leysen, H.; Walter, D.; Clauwaert, L.; Hellemans, L.; van Gastel, J.; Vasudevan, L.; Martin, B.; Maudsley, S. The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease. Int. J. Mol. Sci. 2022, 23, 4387.
  56. Luan, B.; Zhang, Z.; Wu, Y.; Kang, J.; Pei, G. Beta-arrestin2 functions as a phosphorylation-regulated suppressor of UV-induced NF-kappaB activation. EMBO J. 2005, 24, 4237–4246.
  57. Hara, M.R.; Kovacs, J.J.; Whalen, E.J.; Rajagopal, S.; Strachan, R.T.; Grant, W.; Towers, A.J.; Williams, B.; Lam, C.M.; Xiao, K.; et al. A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 2011, 477, 349–353.
  58. Premont, R.T.; Claing, A.; Vitale, N.; Freeman, J.L.; Pitcher, J.A.; Patton, W.A.; Moss, J.; Vaughan, M.; Lefkowitz, R.J. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc. Natl. Acad. Sci. USA 1998, 95, 14082–14087.
  59. Chadwick, W.; Martin, B.; Chapter, M.C.; Park, S.S.; Wang, L.; Daimon, C.M.; Brenneman, R.; Maudsley, S. GIT2 acts as a potential keystone protein in functional hypothalamic networks associated with age-related phenotypic changes in rats. PLoS ONE 2012, 7, e36975.
  60. Martin, B.; Chadwick, W.; Janssens, J.; Premont, R.T.; Schmalzigaug, R.; Becker, K.G.; Lehrmann, E.; Wood, W.H.; Zhang, Y.; Siddiqui, S.; et al. GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging. Front. Endocrinol. 2016, 6, 191.
  61. Siddiqui, S.; Lustig, A.; Carter, A.; Sankar, M.; Daimon, C.M.; Premont, R.T.; Etienne, H.; van Gastel, J.; Azmi, A.; Janssens, J.; et al. Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption. Aging 2017, 9, 706–740.
  62. Lu, D.; Cai, H.; Park, S.S.; Siddiqui, S.; Premont, R.T.; Schmalzigaug, R.; Paramasivam, M.; Seidman, M.; Bodogai, I.; Biragyn, A.; et al. Nuclear GIT2 is an ATM substrate and promotes DNA repair. Mol. Cell. Biol. 2015, 35, 1081–1096.
  63. Maudsley, S.; Patel, S.A.; Park, S.S.; Luttrell, L.M.; Martin, B. Functional signaling biases in G protein-coupled receptors: Game Theory and receptor dynamics. Mini Rev. Med. Chem. 2012, 12, 831–840.
  64. Bohn, L.M.; McDonald, P.H. Seeking Ligand Bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery. Drug Discov. Today Technol. 2010, 7, e37–e42.
  65. Nieto Gutierrez, A.; McDonald, P.H. GPCRs: Emerging anti-cancer drug targets. Cell. Signal. 2018, 41, 65–74.
  66. Nieto, A.; Hara, M.R.; Quereda, V.; Grant, W.; Saunders, V.; Xiao, K.; McDonald, P.H.; Duckett, D.R. βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1. Cell Death Differ. 2020, 27, 1200–1213.
  67. Bayer, P.; Gatenby, R.A.; McDonald, P.H.; Duckett, D.R.; Staňková, K.; Brown, J.S. Coordination games in cancer. PLoS ONE 2022, 17, e0261578.
  68. McDonald, P.H.; Lefkowitz, R.J. Beta-Arrestins: New roles in regulating heptahelical receptors’ functions. Cell. Signal. 2001, 13, 683–689.
  69. Dalle, S.; Ravier, M.A.; Bertrand, G. Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: New therapeutic strategies and consequences for drug screening. Cell. Signal. 2011, 23, 522–528.
  70. Jiang, R.; Song, X.; Bali, P.; Smith, A.; Bayona, C.R.; Lin, L.; Cameron, M.D.; McDonald, P.H.; Kenny, P.J.; Kamenecka, T.M. Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists. Bioorg. Med. Chem. Lett. 2012, 22, 3890–3894.
  71. Pydi, S.P.; Barella, L.F.; Zhu, L.; Meister, J.; Rossi, M.; Wess, J. β-Arrestins as Important Regulators of Glucose and Energy Homeostasis. Annu. Rev. Physiol. 2022, 84, 17–40.
  72. Wess, J. The Two β-Arrestins Regulate Distinct Metabolic Processes: Studies with Novel Mutant Mouse Models. Int. J. Mol. Sci. 2022, 23, 495.
  73. Leysen, H.; van Gastel, J.; Hendrickx, J.O.; Santos-Otte, P.; Martin, B.; Maudsley, S. G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes. Int. J. Mol. Sci. 2018, 19, 2919.
  74. Shen, H.; Wang, L.; Zhang, J.; Dong, W.; Zhang, T.; Ni, Y.; Cao, H.; Wang, K.; Li, Y.; Wang, Y.; et al. ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response. Oncol. Rep. 2017, 37, 761–767.
  75. Sood, R.; Ritov, G.; Richter-Levin, G.; Barki-Harrington, L. Selective increase in the association of the β2 adrenergic receptor, β Arrestin-1 and p53 with Mdm2 in the ventral hippocampus one month after underwater trauma. Behav. Brain Res. 2013, 240, 26–28.
  76. Cai, H.; Cong, W.N.; Ji, S.; Rothman, S.; Maudsley, S.; Martin, B. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Curr. Alzheimer Res. 2012, 9, 5–17.
  77. Siddiqui, S.; Fang, M.; Ni, B.; Lu, D.; Martin, B.; Maudsley, S. Central role of the EGF receptor in neurometabolic aging. Int. J. Endocrinol. 2012, 2012, 739428.
  78. Mezhnina, V.; Ebeigbe, O.P.; Poe, A.; Kondratov, R.V. Circadian Control of Mitochondria in Reactive Oxygen Species Homeostasis. Antioxid. Redox Signal. 2022, 37, 647–663.
  79. Lin, J.; Epel, E. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Res. Rev. 2022, 73, 101507.
  80. Ayala, J.C.; Grismaldo, A.; Sequeda-Castañeda, L.G.; Aristizábal-Pachón, A.F.; Morales, L. Oxidative Stress in ICU Patients: ROS as Mortality Long-Term Predictor. Antioxidants 2021, 10, 1912.
  81. Wang, R.; Ross, C.A.; Cai, H.; Cong, W.N.; Daimon, C.M.; Carlson, O.D.; Egan, J.M.; Siddiqui, S.; Maudsley, S.; Martin, B. Metabolic and hormonal signatures in pre-manifest and manifest Huntington’s disease patients. Front. Physiol. 2014, 5, 231.
  82. Decourt, B.; D’Souza, G.X.; Shi, J.; Ritter, A.; Suazo, J.; Sabbagh, M.N. The Cause of Alzheimer’s Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress. Aging Dis. 2022, 13, 37–60.
  83. Son, J.M.; Lee, C. Aging: All roads lead to mitochondria. Semin. Cell Dev. Biol. 2021, 116, 160–168.
  84. Munro, D.; Pamenter, M.E. Comparative studies of mitochondrial reactive oxygen species in animal longevity: Technical pitfalls and possibilities. Aging Cell 2019, 18, e13009.
  85. Barja, G. Towards a unified mechanistic theory of aging. Exp. Gerontol. 2019, 124, 110627.
  86. Salazar, G. NADPH Oxidases and Mitochondria in Vascular Senescence. Int. J. Mol. Sci. 2018, 19, 1327.
  87. Valente, A.X.C.N.; Adilbayeva, A.; Tokay, T.; Rizvanov, A.A. The Universal Non-Neuronal Nature of Parkinson’s Disease: A Theory. Cent. Asian J. Glob. Health 2016, 5, 231.
  88. Natarajan, V.; Chawla, R.; Mah, T.; Vivekanandan, R.; Tan, S.Y.; Sato, P.Y.; Mallilankaraman, K. Mitochondrial Dysfunction in Age-Related Metabolic Disorders. Proteomics 2020, 20, e1800404.
  89. Yu, C.; Xiao, J.H. The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging. Oxid. Med. Cell Longev. 2021, 2021, 6635460.
  90. Santos-Otte, P.; Leysen, H.; van Gastel, J.; Hendrickx, J.O.; Martin, B.; Maudsley, S. G Protein-Coupled Receptor Systems and Their Role in Cellular Senescence. Comput. Struct. Biotechnol. J. 2019, 17, 1265–1277.
  91. Hendrickx, J.O.; van Gastel, J.; Leysen, H.; Martin, B.; Maudsley, S. High-dimensionality Data Analysis of Pharmacological Systems Associated with Complex Diseases. Pharmacol. Rev. 2020, 72, 191–217.
  92. Lappano, R.; Maggiolini, M. G protein-coupled receptors: Novel targets for drug discovery in cancer. Nat. Rev. Drug Discov. 2011, 10, 47–60.
  93. Milligan, G.; Ulven, T.; Murdoch, H.; Hudson, B.D. G-protein-coupled receptors for free fatty acids: Nutritional and therapeutic targets. Br. J. Nutr. 2014, 111, S3–S7.
  94. Maudsley, S.; Martin, B.; Luttrell, L.M. The origins of diversity and specificity in g protein-coupled receptor signaling. J. Pharmacol. Exp. Ther. 2005, 314, 485–494.
  95. Cai, H.; Cong, W.N.; Daimon, C.M.; Wang, R.; Tschöp, M.H.; Sévigny, J.; Martin, B.; Maudsley, S. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice. PLoS ONE 2013, 8, e76553.
  96. Hauser, A.S.; Attwood, M.M.; Rask-Andersen, M.; Schiöth, H.B.; Gloriam, D.E. Trends in GPCR drug discovery: New agents, targets, and indications. Nat. Rev. Drug. Discov. 2017, 16, 829–842.
  97. Vass, M.; Kooistra, A.J.; Yang, D.; Stevens, R.C.; Wang, M.W.; de Graaf, C. Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol. Sci. 2018, 39, 494–512.
  98. Pándy-Szekeres, G.; Munk, C.; Tsonkov, T.M.; Mordalski, S.; Harpsøe, K.; Hauser, A.S.; Bojarski, A.J.; Gloriam, D.E. GPCRdb in 2018: Adding GPCR structure models and ligands. Nucleic Acids Res. 2018, 46, D440–D446.
  99. Cvicek, V.; Goddard, W.A., 3rd; Abrol, R. Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications. PLoS Comput. Biol. 2016, 12, e1004805.
  100. Rajagopal, S.; Rajagopal, K.; Lefkowitz, R.J. Teaching old receptors new tricks: Biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 2010, 9, 373–386.
  101. Luttrell, L.M.; Maudsley, S.; Gesty-Palmer, D. Translating in vitro ligand bias into in vivo efficacy. Cell. Signal. 2018, 41, 46–55.
  102. Bryja, V.; Gradl, D.; Schambony, A.; Arenas, E.; Schulte, G. Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2007, 104, 6690–6695.
  103. DeWire, S.M.; Kim, J.; Whalen, E.J.; Ahn, S.; Chen, M.; Lefkowitz, R.J. Beta-arrestin-mediated signaling regulates protein synthesis. J. Biol. Chem. 2008, 283, 10611–10620.
  104. Gao, H.; Sun, Y.; Wu, Y.; Luan, B.; Wang, Y.; Qu, B.; Pei, G. Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol. Cell 2004, 14, 303–317.
  105. Kang, J.; Shi, Y.; Xiang, B.; Qu, B.; Su, W.; Zhu, M.; Zhang, M.; Bao, G.; Wang, F.; Zhang, X.; et al. A nuclear function of beta-arrestin1 in GPCR signaling: Regulation of histone acetylation and gene transcription. Cell 2005, 123, 833–847.
  106. Maudsley, S.; Devanarayan, V.; Martin, B.; Geerts, H.; Brain Health Modeling Initiative (BHMI). Intelligent and effective informatic deconvolution of “Big Data” and its future impact on the quantitative nature of neurodegenerative disease therapy. Alzheimers Dement. 2018, 14, 961–975.
  107. Bossers, K.; Wirz, K.T.; Meerhoff, G.F.; Essing, A.H.; van Dongen, J.W.; Houba, P.; Kruse, C.G.; Verhaagen, J.; Swaab, D.F. Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain 2010, 133, 3699–3723.
  108. Liu, X.; Zhao, X.; Zeng, X.; Bossers, K.; Swaab, D.F.; Zhao, J.; Pei, G. β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell Res. 2013, 23, 351–365.
  109. Zhou, Z.; Liao, J.M.; Zhang, P.; Fan, J.B.; Chen, J.; Liang, Y. Parkinson disease drug screening based on the interaction between D(2) dopamine receptor and beta-arrestin 2 detected by capillary zone electrophoresis. Protein Cell 2011, 2, 899–905.
  110. Urs, N.M.; Daigle, T.L.; Caron, M.G. A dopamine D1 receptor-dependent β-arrestin signaling complex potentially regulates morphine-induced psychomotor activation but not reward in mice. Neuropsychopharmacology 2011, 36, 551–558.
  111. Urs, N.M.; Bido, S.; Peterson, S.M.; Daigle, T.L.; Bass, C.E.; Gainetdinov, R.R.; Bezard, E.; Caron, M.G. Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2015, 112, E2517–E2526.
  112. Luan, B.; Zhao, J.; Wu, H.; Duan, B.; Shu, G.; Wang, X.; Li, D.; Jia, W.; Kang, J.; Pei, G. Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 2009, 457, 1146–1149.
  113. Al-Sabah, S.; Al-Fulaij, M.; Shaaban, G.; Ahmed, H.A.; Mann, R.J.; Donnelly, D.; Bünemann, M.; Krasel, C. The GIP receptor displays higher basal activity than the GLP-1 receptor but does not recruit GRK2 or arrestin3 effectively. PLoS ONE 2014, 9, e106890.
  114. Pang, Y.; Zhu, H.; Xu, J.; Yang, L.; Liu, L.; Li, J. β-arrestin-2 is involved in irisin induced glucose metabolism in type 2 diabetes via p38 MAPK signaling. Exp. Cell Res. 2017, 360, 199–204.
  115. Gesty-Palmer, D.; Flannery, P.; Yuan, L.; Corsino, L.; Spurney, R.; Lefkowitz, R.J.; Luttrell, L.M. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci. Transl. Med. 2009, 1, 1ra1.
  116. Urs, N.M.; Peterson, S.M.; Caron, M.G. New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy. Biol. Psychiatry 2017, 81, 78–85.
  117. Park, S.M.; Chen, M.; Schmerberg, C.M.; Dulman, R.S.; Rodriguiz, R.M.; Caron, M.G.; Jin, J.; Wetsel, W.C. Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice. Neuropsychopharmacology 2016, 41, 704–715.
  118. Anckaerts, C.; van Gastel, J.; Leysen, V.; Hinz, R.; Azmi, A.; Simoens, P.; Shah, D.; Kara, F.; Langbeen, A.; Bols, P.; et al. Image-guided phenotyping of ovariectomized mice: Altered functional connectivity, cognition, myelination, and dopaminergic functionality. Neurobiol. Aging 2019, 74, 77–89.
  119. Chadwick, W.; Zhou, Y.; Park, S.S.; Wang, L.; Mitchell, N.; Stone, M.D.; Becker, K.G.; Martin, B.; Maudsley, S. Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS ONE 2010, 5, e14352.
  120. Rasheed, N.; Wang, X.; Niu, Q.T.; Yeh, J.; Li, B. Atm-deficient mice: An osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis. Hum. Mol. Genet. 2006, 15, 1938–1948.
  121. Wang, X.; Liao, S.; Nelson, E.R.; Schmalzigaug, R.; Spurney, R.F.; Guilak, F.; Premont, R.T.; Gesty-Palmer, D. The cytoskeletal regulatory scaffold protein GIT2 modulates mesenchymal stem cell differentiation and osteoblastogenesis. Biochem. Biophys. Res. Commun. 2012, 425, 407–412.
  122. Van Gastel, J.; Hendrickx, J.O.; Leysen, H.; Martin, B.; Veenker, L.; Beuning, S.; Coppens, V.; Morrens, M.; Maudsley, S. Enhanced Molecular Appreciation of Psychiatric Disorders Through High-Dimensionality Data Acquisition and Analytics. Methods Mol. Biol. 2019, 2011, 671–723.
  123. Lee, S.A.; Huang, K.C. Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia. BMC Med. Genom. 2016, 9, 68.
  124. Appleton, K.M.; Lee, M.H.; Alele, C.; Alele, C.; Luttrell, D.K.; Peterson, Y.K.; Morinelli, T.A.; Luttrell, L.M. Biasing the parathyroid hormone receptor: Relating in vitro ligand efficacy to in vivo biological activity. Methods Enzymol. 2013, 522, 229–262.
  125. Gesty-Palmer, D.; Luttrell, L.M. Refining efficacy: Exploiting functional selectivity for drug discovery. Adv. Pharmacol. 2011, 62, 79–107.
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