Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin

Feinstein, Timothy N.; Yui, Naofumi; Webber, Matthew J.; Wehbi, Vanessa L.; Stevenson, Hilary P.; King, Jennifer; Hallows, Kenneth R.; Brown, Dennis; Bouley, Richard; Vilardaga, Jean-Pierre

doi:10.1074/jbc.m112.445098

Cited by 188 publications

(190 citation statements)

References 56 publications

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…4C). βarr1 (WT) did not have a significant effect on V 2 R-stimulated cAMP signaling, which agrees with previous work (23). Most strikingly, expression of βarr1 (ΔFLR) did not lead to any significant desensitization of G protein signaling for any of the GPCRs tested (Fig.…”

Section: Resultssupporting

confidence: 80%

Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis

Cahill

Thomsen

Tarrasch

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

291

290

View full text Add to dashboard Cite

β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-βarr complexes: the "tail" conformation, with βarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the "core" conformation, where, in addition to the phosphorylated C-terminal tail, βarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of βarrs is unknown. Here, we created a mutant form of βarr lacking the "finger-loop" region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and βarr signaling but not desensitization of G protein signaling. Thus, the two GPCR-βarr conformations can carry out distinct functions.O ver the past decade, significant efforts have been made to understand the molecular properties and regulatory mechanisms that control the function of β-arrestin (βarr) interactions with G protein-coupled receptors (GPCRs) (1, 2). Once activated, GPCRs initiate a highly conserved signaling and regulatory cascade marked by interactions with: (i) heterotrimeric G proteins, which mediate their actions largely by promoting second-messenger generation (3); (ii) GPCR kinases (GRKs), which phosphorylate activated conformations of receptors (4); and (iii) βarrs, which bind to the phosphorylated receptors to mediate desensitization of G protein signaling and receptor internalization (5, 6). In addition to their canonical function of desensitization and internalization, βarrs have been appreciated as independent signaling units by virtue of their crucial role as both adaptors and scaffolds for an increasing number of signaling pathways (7-11).There are two driving forces that mediate βarr interactions with an activated GPCR: phosphorylation of the C-terminal tail of the receptor by GRKs and/or binding to the transmembrane core of the receptor. How each of these interactions contributes to βarr functionality remains unclear. Moreover, GPCRs tend to either interact with βarr transiently, termed "class A" GPCRs [e.g., β 2 -adrenergic receptor (β 2 AR)], or tightly, known as "class B" GPCRs [e.g., vasopressin type 2 receptor (V 2 R)]. For the current study, we use a previously described chimeric β 2 V 2 R construct, which comprises the β 2 AR with its C-terminal tail exchanged with the V 2 R C-terminal tail (12-14). The β 2 V 2 R construct provides an ideal system for studying a GPCR-βarr complex in vitro, because it maintains identical pharmacological properties to the WT β 2 AR and has a robustly increased class B affinity for βarr1, which allows stable β 2 V 2 R-βarr complexes to be formed and purified.Structural insights have shed some light onto the complexity of the interaction between GPCRs and βarrs. A recent struc...

show abstract

Section: Resultssupporting

confidence: 80%

Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis

Cahill

Thomsen

Tarrasch

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

291

290

View full text Add to dashboard Cite

show abstract

“…Mature receptors are located in the Golgi network and at the plasma membrane. To maintain stable levels of V2Rs, redundant receptors from the plasma membrane are internalized and degraded in the lysosomes (15,31,34).…”

Section: V2r Compared With Other Receptors In the Avp/ot Familymentioning

confidence: 99%

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors

Juul

Bichet

Nielsen

et al. 2014

American Journal of Physiology-Renal Physiology

122

View full text Add to dashboard Cite

Juul KV, Bichet DG, Nielsen S, Nørgaard JP. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 306: F931-F940, 2014. First published March 5, 2014 doi:10.1152/ajprenal.00604.2013.-The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine concentrating mechanism through the AVP/V2 type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongly support the existence of an extrarenal V2R. The clinical importance of the extrarenal V2R spans widely from stimulation of coagulation factor in the endothelium to as yet untested potential therapeutic targets. These include V2R-regulated membranous fluid turnover in the inner ear, V2R-regulated mitogensis and apoptosis in certain tumor tissues, and numerous other cell types where the physiological role of V2Rs still requires further research. Here, we review current evidence on the physiological and pathophysiological functions of renal and extrarenal V2Rs. These functions of V2R are important, not only in rare diseases with loss or gain of function of V2R but also in relation to the recent use of nonpeptide V2R antagonists to treat hyponatremia and possibly retard the growth of cysts and development of renal failure in autosomal dominant polycystic kidney disease. The main functions of V2R in principal cells of the collecting duct are water, salt, and urea transport by modifying the trafficking of aquaporin 2, epithelial Na ϩ channels, and urea transporters and vasodilation and stimulation of coagulation factor properties, mainly seen with pharmacological doses of 1-desamino-8-D-AVP. The AVPR2 gene is located on the X chromosome, in a region with high probability of escape from inactivation; this may lead to phenotypic sex differences, with females expressing higher levels of transcript than males. vasopressin V 2 receptor; arginine vasopressin V2 receptor; arginine vasopressin; desmopressin; extrarenal vasopressin V 2 receptor THE PURPOSE OF THIS REPORT is to review current evidence on the physiological and pathophysiogical functions of renal and extrarenal arginine vasopressin (AVP) type 2 receptors, referred to as V2Rs (Fig. 1).AVP is an important neurohypophyseal nonapeptide that, via its three receptor types, is primarily responsible for regulating osmotic homeostasis of body fluids, volume homeostasis, and vasoconstriction in addition to an array of central functions such as memory and learning (17,29). In addition to these endocrine functions, AVP also contributes to regulating mitogenesis, cell survival, and death (apoptosis) (77).AVP is released from its storage site in the posterior pituitary (Fig. 2) by highly sensitive osmotic stimuli, specifically by a Ͻ1-2% increase in plasma osmolarity, as originally detailed in the 1940s through classic research by Prof. E. B. Verney (125). AVP release may also ...

show abstract

“…PTHR and thyroid-stimulating receptor were the first mammalian GPCRs demonstrated to signal persistently through cAMP upon receptor redistribution to endosomes (37,38). As noted above, other receptors have since been shown to behave similarly (32,39,40). Endosomal cAMP signaling is terminated when the acidic environment of the endosome causes ligand dissociation (41), after which the receptor interacts with the endosomal retromer complex for signal termination and subsequent trafficking (42,43).…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Noncanonical Control of Vasopressin Receptor Type 2 Signaling by Retromer and Arrestin

Cited by 188 publications

References 56 publications

Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis

Distinct conformations of GPCR–β-arrestin complexes mediate desensitization, signaling, and endocytosis

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors

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

Contact Info

Product

Resources

About