Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability

doi:10.1016/j.lfs.2003.09.024

Life Sciences

Volume 74, Issues 2–3, 5 December 2003, Pages 379-389

https://doi.org/10.1016/j.lfs.2003.09.024 Get rights and content

Abstract

The alpha-1 adrenergic receptors (α₁ARs) play important roles in normal physiology and in many disease states, and understanding their signaling pathways and regulatory mechanisms is thus of considerable relevance, in particular for identifying pharmacological targets for therapeutic modulation. The expression, function, localization, trafficking, and stability of these receptors are all subject to complex regulation by diverse molecular mechanisms. This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the alpha-1B adrenergic receptor (α_1BAR) subtype and on changes in its stability that are likely to be involved in regulating receptor expression. The role(s) of protein kinase C in α_1BAR sequestration, endocytosis, and extracellular signal-regulated kinase (ERK) activation are summarized, and evidence for α_1BAR localization in caveolae/rafts is presented. Receptor structural domains involved in the multiple steps and mechanisms of agonist-induced desensitization are described. Finally, aspects of α_1BAR structural stability that appear to control its drug-induced up- and down-regulation are discussed. Our understanding of regulation for the α_1BAR subtype provides a model for studies of the differential regulation of the other α₁AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states.

Introduction

The alpha-1B adrenergic receptors (α_1BARs), like the prototypical beta-2 adrenergic receptors (β₂ARs) and most other G protein-coupled receptors (GPCRs), are not only activated by agonist binding but also undergo a complex series of adaptive changes generally referred to as desensitization. These include rapid decreases in receptor function (uncoupling), changes in subcellular localization (internalization), as well as slower decreases in the level of expression of receptors detectable by radioligand binding (down-regulation). This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the α_1BARs and on changes in receptor stability that are likely to be involved in regulating receptor expression. Our understanding of regulation for the α_1BAR subtype provides a model for future studies of the differential regulation of the other α₁AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states.

Section snippets

α_1BAR function and agonist-induced uncoupling

The α_1BARs are one of three subtypes of α₁ARs, the other two being α_1AARs and α_1DARs; these together constitute one of three families of adrenergic receptors, the other two being the α₂ARs and the βARs. The α_1BARs, as well as the α_1AARs and α_1DARs, couple to the G_q/11 family of G proteins, and agonist binding leads to activation of phospholipase C (PLC) and stimulation of phosphoinositide (PI) hydrolysis, with increases in intracellular free calcium and activation of protein kinase C (PKC) as

α_1BAR internalization: sequestration, endocytosis, and the role of PKC

In unstimulated cells, α_1BARs are localized primarily in the plasma membrane, but agonist exposure leads to rapid changes in cell surface accessibility and membrane localization. Localization and trafficking of α_1BARs can be detected by their accessibility to hydrophilic ligands that do not readily cross cell membranes, by changes in their distribution on sucrose density gradient centrifugation, and more recently by confocal fluorescence microscopy (CFM) localization with either receptor

α_1BAR C-tail domains involved in internalization and down-regulation

Several recent studies clearly demonstrate critical roles of specific C-tail domains in all aspects of α_1BAR desensitization. Truncation of the hamster α_1BAR after Arg-368 (T368) did not greatly alter its binding or functional properties, but receptor phosphorylation and desensitization were largely eliminated (Lattion et al., 1994). Further studies identified Ser-404, -408, and -410 as the major sites for GRK phosphorylation and desensitization, and Ser-394 and -400 as the sites for PKC

α_1BAR signaling to extracellular signal-regulated kinases (ERKs)

Similar to many other GPCRs, α_1BAR activation can lead to phosphorylation and activation of multiple members of the mitogen-activated protein kinase (MAPK) family, critical mediators of transcription factor regulation controlling cell growth, apoptosis, and differentiation Auer et al., 1998, Zhong and Minneman, 1999a, Keffel et al., 2000, Chalothorn et al., 2002. Because of multiple studies suggesting a requirement of receptor endocytosis for GPCR activation of the extracellular

α_1BAR localization in caveolae or membrane lipid rafts

The ability of α_1BARs to sequester within the plasma membrane without endocytosing into intracellular vesicles, together with their apparent ability to down-regulate their binding capacity without being internalized and delivered to classical degradative compartments, led us to explore the possible localization or trafficking of α_1BARs into alternate plasma membrane compartments. Caveolae or membrane lipid rafts are specialized membrane domains that are known to regulate receptor signaling

Regulation of α_1BAR structural stability and α_1BAR up- and down-regulation

Studies of the down-regulation properties of the G protein coupling-defective IC3-mutated Δ12 and Δ5 α_1BARs revealed the unexpected result that agonist exposure led to an up-regulation of [³H]prazosin-binding activity rather than down-regulation (Wang et al., 2002). The mechanism(s) involved in this up-regulation have been further investigated (Prinster et al., 2003). Multiple studies eliminated various transcriptional up-regulation mechanisms, and the fact that up-regulation was not blocked by

Concluding remarks

The studies summarized here delineate many of the important mechanisms regulating localization, trafficking, and stability for α_1BARs, the best characterized of the α₁AR subtypes. Though not discussed here, several recent studies indicate that the functions, localization and trafficking, and other aspects of regulation can be quite different for the three α₁AR subtypes. For example, the α_1DAR is reported to be primarily intracellular, and it also appears to exhibit considerable constitutive

Acknowledgements

These studies were supported by NIH Research Grant GM34500.

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Pour cela, dix sujets masculins sédentaires ont été recrutés, âgés de 30 à 39 ans, avec un indice de masse corporelle (IMC) élevé. Chaque participant a été évalué en quatre sessions distinctes. La première séance consistait à déterminer la puissance aérobie maximale (PAP). Les participants aux sessions suivantes ont exécuté trois protocoles d’exercices équivalents, consistant chacun en trois séances d’exercice de 15 minutes séparées par 5 minutes de repos entre les deux. Le protocole à intensité constante comprenait des périodes d’exercice à 55 % de PAP, tandis que les deux autres (protocoles à intensité croissante et décroissante) consistaient en des périodes d’exercice à 40, 55 et 70 % de PAP dans un ordre croissant ou décroissant respectivement.
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PKC-isoform specific regulation of receptor desensitization and KCNQ1/KCNE1 K<sup>+</sup> channel activity by mutant α<inf>1B</inf>-adrenergic receptors
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Within this time frame, several mechanism are proposed to regulate receptor internalization, e.g. the interaction of α1B-AR with β-arrestin and the clathrin adaptor complex AP2 [17] or with Rab4 and Rab5 proteins [39]. Mutational studies on the hamster α1B-AR identified the aa 403–425 domain of the C-tail as critical for internalization [41]. This domain contains the GRK phosphorylation sites (for the human ortholog S406,S410,S412) that seem to be essential for receptor internalization since coexpression of a dominant-negative GRK2 markedly decreased receptor internalization [42].
Activation of a specific protein kinase C (PKC) isoform during stimulation of G_q protein-coupled receptors (G_qPCRs) is determined by homologous receptor desensitization that controls the spatiotemporal formation of downstream G_q signalling molecules. Furthermore, G_qPCR-activated PKC isoforms specifically regulate receptor activity via a negative feedback mechanism.
In the present study, we investigated the contribution of several phosphorylation sites in the α_1B-adrenergic receptor (α_1B-AR) for PKC and G protein coupled receptor kinase 2 (GRK2) to homologous receptor desensitization and effector modulation. We analyzed signalling events downstream to human wildtype α_1B-ARs and α_1B-ARs lacking PKC or GRK2 phosphorylation sites (Δ391–401, α_1B-ΔPKC-AR and Δ402–520, α_1B-ΔGRK-AR) by means of FRET-based biosensors in HEK293 that served as online-assays of receptor activity. K⁺ currents through KCNQ1/KCNE1 channels (I_Ks), which are regulated by both phosphatidylinositol 4,5-bisphosphate (PIP₂)-depletion and/or phosphorylation by PKC, were measured as a functional readout of wildtype and mutant α_1B-AR receptor activity.
As a novel finding, we provide evidence that deletion of PKC and GRK2 phosphorylation sites in α_1B-ARs abrogates the contribution of PKCα to homologous receptor desensitization. Instead, the time course of mutant receptor activity was specifically modulated by PKCβ. Mutant α_1B-ARs displayed pronounced homologous receptor desensitization that was abolished by PKCβ-specific pharmacological inhibitors.
I_Ks modulation during stimulation of wildtype and mutant α_1B-ARs displayed transient inhibition and current facilitation after agonist withdrawal with reduced capability of mutant α_1B-ARs to induce I_Ks inhibition. Pharmacological inhibition of the PKCβ isoform did not augment I_Ks reduction by mutant α_1B-ARs, but shifted I_Ks modulation towards current facilitation. Coexpression of an inactive (dominant-negative) PKCδ isoform (DN-PKCδ) abolished I_Ks facilitation in α_1B-ΔGRK-AR-expressing cells, but not in α_1B-ΔPKC-AR-expressing cells. The data indicate that the differential modulation of I_Ks activity by α_1B-ΔGRK- and α_1B-ΔPKC-receptors is attributed to the activation of entirely distinct novel PKC isoforms.
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Sites phosphorylated in human α<inf>1B</inf>-adrenoceptors in response to noradrenaline and phorbol myristate acetate
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Pioneer contributions by Cotecchia and coworkers, using receptor mutants with deletions and mutagenesis of specific sites, together with functional studies, identified that relevant phosphorylation sites for hamster α1B-AR are located in a cluster at the Ctail, which seem to be targeted by G protein-coupled receptor kinases (GRK) and PKC [30,32]. In addition, the group of Toews [35,36] has observed that, in the hamster receptor, two domains play key roles in receptor internalization/down regulation. Using deletions and site-directed mutagenesis, these authors observed that some mutated receptors internalize but do not down-regulate, other mutants that down-regulate without internalization, and that there are also receptors defective in both internalization and down-regulation [35].
Phosphorylation of the human α_1B-adrenergic receptor (fused with the green fluorescent protein) was studied employing the inducible Flp-ln HEK293 T-Rex system for expression. Serine/alanine substitutions were performed in five sites corresponding to those previously identified as phosphorylation targets in the hamster ortholog. Desensitization was decreased in these mutants but receptor phosphorylation was still clearly detected. The protein phosphorylation of the wild-type receptor (fused to the green fluorescent protein) was studied, using mass spectrometry, under baseline and stimulated conditions (noradrenaline or phorbol myristate acetate). Basal phosphorylation was detected at sites located at the intracellular loop 3 and carboxyl terminus, and the number of sites detected increased under agonist activation and stimulation of protein kinase C. The phosphorylation patterns differed under the distinct conditions. Three of the phosphorylation sites detected in this work corresponded to those observed in the hamster receptor. The phosphorylation sites detected included the following: a) at the intracellular loop 3: serines 246, 248, 257, 267, and 277; and threonines 252, 264, and 268, and b) at the carboxyl terminus: serines 396, 400, 402, 406, 423, 425, 427, 455, and 470, and threonines 387, 392, 420, and 475. Our data indicate that complex phosphorylation patterns exist and suggest the possibility that such differences could be relevant in receptor function and subcellular localization.
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Although truncation studies demonstrated that homologous desensitization of the α1B-AR depends unequivocally on PKC-induced phosphorylation of serine residues in the C terminus (35, 40), conflicting results were reported upon the contribution of GRK to α1B-AR phosphorylation and desensitization (41, 42), depending on the cell expression system. Mutational studies on hamster α1B-AR indicate that PKC activation and phosphorylation of residues within the C-tail promote rapid receptor internalization (43). More recent studies propose that interactions of α1B-AR with β-arrestin and the clathrin adaptor complex AP2 (36) or with Rab4 and Rab5 proteins that are associated with early endosomes (25) regulate receptor internalization.
Activation of G_q protein-coupled receptors (G_qPCRs) might induce divergent cellular responses, related to receptor-specific activation of different branches of the G_q signaling pathway. Receptor-specific desensitization provides a mechanism of effector modulation by restricting the spatiotemporal activation of signaling components downstream of G_q. We quantified signaling events downstream of G_qPCR activation with FRET-based biosensors in CHO and HEK 293 cells. KCNQ1/KCNE1 channels (I_Ks) were measured as a functional readout of receptor-specific activation. Activation of muscarinic M₁ receptors (M₁-Rs) caused robust and reversible inhibition of I_Ks. In contrast, activation of α_1B-adrenergic receptors (α_1B-ARs) induced transient inhibition of I_Ks, which turned into delayed facilitation after agonist withdrawal. As a novel finding, we demonstrate that G_qPCR-specific kinetics of I_Ks modulation are determined by receptor-specific desensitization, evident at the level of Gα_q activation, phosphatidylinositol 4,5-bisphosphate (PIP₂) depletion, and diacylglycerol production. Sustained I_Ks inhibition during M₁-R stimulation is attributed to robust membrane PIP₂ depletion, whereas the rapid desensitization of α_1B-AR delimits PIP₂ reduction and augments current activation by protein kinase C (PKC). Overexpression of Ca²⁺-independent PKCδ did not affect the time course of α_1B-AR-induced diacylglycerol formation, excluding a contribution of PKCδ to α_1B-AR desensitization. Pharmacological inhibition of Ca²⁺-dependent PKC isoforms abolished fast α_1B receptor desensitization and augmented I_Ks reduction, but did not affect I_Ks facilitation. These data indicate a contribution of Ca²⁺-dependent PKCs to α_1B-AR desensitization, whereas I_Ks facilitation is induced by Ca²⁺-independent PKC isoforms. In contrast, neither inhibition of Ca²⁺-dependent/Ca²⁺-independent isoforms nor overexpression of PKCδ induced M₁ receptor desensitization, excluding a contribution of PKC to M₁-R-induced I_Ks modulation.
Characterization of the α<inf>1</inf>-adrenoceptor subtype activating extracellular signal-regulated kinase in submandibular gland acinar cells
2008, European Journal of Pharmacology
α₁-Adrenoceptors and extracellular signal-regulated kinases 1 and 2 (ERK1/2) regulate salivary secretion. However, whether α₁-adrenoceptors couple to ERK1/2 activation and the specific α₁-adrenoceptor subtypes involved in salivary glands is unknown. Western blotting of ERK1/2 phosphorylation showed phenylephrine activated ERK1/2 by 2–3-fold in submandibular gland slices and 3–4-fold in submandibular acinar (SMG-C10) cells with an EC₅₀ of 2.7 ± 2 μM. ERK1/2 activation was blocked by either prazosin or HEAT, indicating α₁-adrenoceptors stimulate ERK1/2 in native glands and SMG-C10 cells. Inhibition of [¹²⁵I]HEAT binding by 5-methylurapidil (selective for α_1A over α_1B/α_1D), but not BMY 7378 (selective for α_1D over α_1A/α_1B), was biphasic and best-fit by a two-site binding model with K_i_H and K_i_L values for 5-methylurapidil of 0.64 ± 0.3 and 91 ± 7 nM, respectively, in SMG-C10 membranes. From these binding data, we obtained subtype-selective concentrations of 5-methylurapidil to determine the α₁-adrenoceptor subtype/s activating ERK1/2 in SMG-C10 cells. 5-methylurapidil (20 nM) did not affect phenylephrine- or A-61603- (α_1A-selective agonist) induced ERK1/2 activation; whereas, 30 μM chloroethylclonidine (α_1B-selective antagonist) inhibited ERK1/2 activation by phenylephrine, indicating α_1B-adrenoceptors, but not α_1A-adrenoceptors, activate ERK1/2 in submandibular cells. We also examined α₁-adrenoceptor location and dependence on cholesterol-rich microdomains for activating ERK1/2. Sucrose density gradient centrifugation showed 71 ± 3% of α₁-adrenoceptor binding sites were in plasma membranes. Cholesterol-disrupting agents filipin and methyl-β-cyclodextrin inhibited phenylephrine-stimulated ERK1/2. These results show only α_1B-adrenoceptors activate ERK1/2 and suggest subtype-specific ERK1/2 signaling by α_1B-adrenoceptors may be determined by localization to cholesterol-rich microdomains in submandibular cells.
Signal transduction and regulation: Are all α<inf>1</inf>-adrenergic receptor subtypes created equal?
2007, Biochemical Pharmacology
Citation Excerpt :
Moreover, the regulation of receptor expression can also be induced by molecules which do not directly act on the receptor, i.e. heterologous regulation. As the regulation of α1-AR expression in general has been reviewed previously [90,93,94], we will focus on studies comparing the regulation of two or more α1-AR subtypes. A subtype-selective regulation of α1-ARs has been demonstrated in many tissues, e.g. related to physiological factors such as sex [95], ageing [96] or β-AR stimulation [97].
The current manuscript reviews the evidence whether and how subtypes of α₁-adrenergic receptors, i.e. α_1A-, α_1B- and α_1D-adrenergic receptors, differentially couple to signal transduction pathways and exhibit differential susceptibility to regulation. In both regards studies in tissues or cells natively expressing the subtypes are hampered because the relative expression of the subtypes is poorly controlled and the observed effects may be cell-type specific. An alternative approach, i.e. transfection of multiple subtypes into the same host cell line overcomes this limitation, but it often remains unclear whether results in such artificial systems are representative for the physiological situation. The overall evidence suggests that indeed subtype-intrinsic and cell type-specific factors interact to direct α₁-adrenergic receptor signaling and regulation. This may explain why so many apparently controversial findings have been reported from various tissues and cells. One of the few consistent themes is that α_1D-adrenergic receptors signal less effectively upon agonist stimulation than the other subtypes, most likely because they exhibit spontaneous internalization.

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Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability

Abstract

Introduction

Section snippets

α1BAR function and agonist-induced uncoupling

α1BAR internalization: sequestration, endocytosis, and the role of PKC

α1BAR C-tail domains involved in internalization and down-regulation

α1BAR signaling to extracellular signal-regulated kinases (ERKs)

α1BAR localization in caveolae or membrane lipid rafts

Regulation of α1BAR structural stability and α1BAR up- and down-regulation

Concluding remarks

Acknowledgements

FEBS Letters

Biochemical and Biophysical Research Communications

Journal of Biological Chemistry

Journal of Biological Chemistry

Journal of Biological Chemistry

European Journal of Pharmacology

Journal of Biological Chemistry

Life Sciences

Biochemical and Biophysical Research Communications

Journal of Biological Chemistry

Journal of Biological Chemistry

Pharmacology and Therapeutics

Biochemical and Biophysical Research Communications

Journal of Biological Chemistry

Journal of Biological Chemistry

Molecular Pharmacology

Journal of Biological Chemistry

Journal of Biological Chemistry

European Journal of Pharmacology

European Journal of Pharmacology

The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H2 receptor

Molecular Pharmacology

Differences in the cellular localization and agonist-mediated internalization properties of the alpha(1)-adrenoceptor subtypes

Molecular Pharmacology

Regulatory mechanisms of α1B-adrenergic receptor function

Biochemical Society Transactions

Effects of agonist and phorbol ester on adrenergic receptors of DDT1 MF- 2 cells

Journal of Pharmacology and Experimental Therapeutics

Evidence for a1-adrenergic receptor internalization in DDT1 MF-2 cells following exposure to agonists plus protein kinase C activators

Molecular Pharmacology

Induction of mutant dynamin specifically blocks endocytic coated vesicle formation

Journal of Cell Biology

β-Arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2

Journal of Cell Biology

Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling

Pharmacological Reviews

α_1BAR function and agonist-induced uncoupling

α_1BAR internalization: sequestration, endocytosis, and the role of PKC

α_1BAR C-tail domains involved in internalization and down-regulation

α_1BAR signaling to extracellular signal-regulated kinases (ERKs)

α_1BAR localization in caveolae or membrane lipid rafts

Regulation of α_1BAR structural stability and α_1BAR up- and down-regulation

The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H₂ receptor

Regulatory mechanisms of α_1B-adrenergic receptor function

Effects of agonist and phorbol ester on adrenergic receptors of DDT₁ MF- 2 cells

Evidence for a1-adrenergic receptor internalization in DDT₁ MF-2 cells following exposure to agonists plus protein kinase C activators