Emerging Functional Divergence of β-Arrestin Isoforms in GPCR Function

Srivastava, Ashish; Gupta, Bhupendra; Gupta, Charu; Shukla, Arun K.

doi:10.1016/j.tem.2015.09.001

Cited by 129 publications

(118 citation statements)

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“…Interestingly, both b-arrestin 1 and 2 siRNA were effective at reducing ERK1/2 activity (Mahavadi et al, 2014). Differences in the roles of b-arrestin 1/2 among studies are likely a result of different cell systems or different strategies used; however, overlapping, as well as divergent roles of b-arrestins, have been well documented in many cell models, receptors, and tissues (Srivastava et al, 2015) (Fig. 2).…”

Section: Cb 1 Rs and B-arrestin-mediated Signalingmentioning

confidence: 99%

“…More recently, a third function was described; b-arrestin recruitment to phosphorylated receptors initiates a G proteinindependent wave of signaling that results in the activation of multiple effectors including ERK, c-Jun N-terminal kinase (JNK), and SRC proto-oncogene nonreceptor tyrosine kinase (Src), among others (Gurevich and Gurevich, 2006;DeWire et al, 2007;Luttrell and Gesty-Palmer, 2010;Shenoy and Lefkowitz, 2011). Not surprisingly, b-arrestin function as signaling facilitator is specific and dependent on the type of receptor, ligand, and cellular environment (Whalen et al, 2011;Srivastava et al, 2015).…”

Section: Multifaceted B-arrestinsmentioning

confidence: 99%

“…Over the last 5 years, we have witnessed a significant increase in our knowledge of the mechanisms and signaling cascades controlled by the multifunctional scaffold protein, b-arrestin, downstream from the CB 1 R. In general, mounting evidence indicates that signaling cascades can be directly regulated by b-arrestin 1, whereas CB 1 R endocytosis is regulated by b-arrestin 2 (Ahn et al, 2013;Gyombolai et al, 2013;Srivastava et al, 2015;Delgado-Peraza et al, 2016). These signaling cascades control specific gene transcription, providing an initial glimpse to the physiologic roles of b-arrestin-mediated signaling.…”

Section: Future Directionsmentioning

confidence: 99%

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The Multiple Waves of Cannabinoid 1 Receptor Signaling

Nogueras-Ortiz

Yudowski

2016

Mol Pharmacol

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The cannabinoid 1 receptor (CB 1 R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system, with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB 1 Rs may signal in three different spatiotemporal waves. The first wave, which is transient (,10 minutes) and initiated by heterotrimeric G proteins, is followed by a second wave (.5 minutes) that is mediated by b-arrestins. The third and final wave occurs at intracellular compartments and could be elicited by G proteins or b-arrestins. This complexity presents multiple challenges, including the correct classification of receptor ligands, the identification of the signaling pathways regulated by each wave, and the underlying molecular mechanisms and physiologic impacts of these waves. Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system and other GPCRs. Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from the CB 1 R. The identification of receptor mutations that can bias signaling to specific pathways and the use of siRNA technology have been key tools to identifying which signaling cascades are controlled by G proteins or b-arrestins. Here, we review our current knowledge on CB 1 R signaling, with particular emphasis on the mechanisms and cascades mediated by b-arrestins downstream from the CB 1 R.

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Section: Cb 1 Rs and B-arrestin-mediated Signalingmentioning

confidence: 99%

Section: Multifaceted B-arrestinsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

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The Multiple Waves of Cannabinoid 1 Receptor Signaling

Nogueras-Ortiz

Yudowski

2016

Mol Pharmacol

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“…The functional repertoire of GPCR-βarr signalling axis is quite broad and spans a wide range of cellular and physiological processes3121314. This is primarily mediated by a large number of interactions of βarrs and their abilities to scaffold a wide array of kinases and other signalling molecules1213.…”

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confidence: 99%

Functional competence of a partially engaged GPCR–β-arrestin complex

et al. 2016

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G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR–βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of βarr first and then seven transmembrane core of the receptor engages with βarr. It is currently unknown whether fully engaged GPCR–βarr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric β2V2R with βarr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a βarr biased ligand, does not promote detectable engagement between βarr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-βarr interaction and provide novel insights into GPCR signalling and regulatory paradigms.

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“…Class A receptors, such as the prototype ␤ 2 AR, preferentially but transiently bind ␤-arrestin-2, from which they rapidly dissociate, and following dephosphorylation, recycle through endosomes to the plasma membrane. Class B receptors, which include the PTHR, type 1 angiotensin II receptor, and vasopressin type 2 receptor, display similar affinities for ␤-arrestin-1 and ␤-arrestin-2, with which they remain associated, returning to the cell membrane more slowly (27,28). It is well established that arrestin binding to many class B GPCRs, such as the type 1 angiotensin II receptor, desensitizes G protein signaling in the same manner as it does with prototype class A receptors, as with the ␤ 2 AR (29).…”

mentioning

confidence: 99%

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

McGarvey¹,

Xiao²,

Bowman³

et al. 2016

Journal of Biological Chemistry

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The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domaincontaining proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner. PTH treatment enriched endosomal PTHR. SNX27 contains a PDZ domain and serves as a cargo selector for the retromer complex. VPS26, VPS29, and VPS35 retromer subunits were isolated with PTHR in endosomes from cells stimulated with PTH. Molecular dynamics and protein binding studies establish that PTHR and SNX27 interactions depend on the PDZ recognition motif in PTHR and the PDZ domain of SNX27. Depletion of either SNX27 or VPS35 or actin depolymerization decreased the rate of PTHR recycling following agonist stimulation. Mutating the PDZ ligand of PTHR abolished the interaction with SNX27 but did not affect the overall rate of recycling, suggesting that PTHR may directly engage the retromer complex. Coimmunoprecipitation and overlay experiments show that both intact and mutated PTHR bind retromer through the VPS26 protomer and sequentially assemble a ternary complex with PTHR and SNX27. SNX27-independent recycling may involve N-ethylmaleimide-sensitive factor, which binds both PDZ intact and mutant PTHRs. We conclude that PTHR recycles rapidly through at least two pathways, one involving the ASRT complex of actin, SNX27, and retromer and another possibly involving N-ethylmaleimide-sensitive factor.

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Emerging Functional Divergence of β-Arrestin Isoforms in GPCR Function

Cited by 129 publications

References 100 publications

The Multiple Waves of Cannabinoid 1 Receptor Signaling

The Multiple Waves of Cannabinoid 1 Receptor Signaling

Functional competence of a partially engaged GPCR–β-arrestin complex

Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling

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