Molecular Basis for Interactions of G Protein (2007)
Subunits With Effectors, Carolyn E. Ford, Nikolai P. Skiba, Hyunsu Bae, Yehia Daaka, Eitan Reuveny, ...
free Ga and Gbg subunits that can activate various effectors (1). Effector proteins of the Gbg complex include phospholipases (2), adenylyl cyclases (3), ion channels (4), G protein--coupled receptor...
Whalen, Erin J., Foster, Matthew W., Matsumoto, Akio, Ozawa, Kentaro, Violin, Jonathan D., Que, Loretta G., ...
β-adrenergic receptors (β-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein...
Whalen, Erin J., Foster, Matthew W., Matsumoto, Akio, Ozawa, Kentaro, Violin, Jonathan D., Que, Loretta G., ...
β-adrenergic receptors (β-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein...
Cong, Mei, Perry, Stepehn J., Lin, Fang-Tsyr, Fraser, Iain D., Hu, Liaoyuan A., Chen, Wei, ...
The beta 2 adrenergic receptor (beta 2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The...
Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity
Claing, Audrey, Perry, Stephen J., Achiriloaie, Mircea, Walker, Julia K. L., Albanesi, Joseph P., Lefkowitz, Robert J., ...
Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1. This protein initially was identified as an interacting...
Receptor and Gβγ isoform-specific interactions with G protein-coupled receptor kinases
Daaka, Yehia, Pitcher, Julie A., Richardson, Mark, Stoffel, Robert H., Robishaw, Janet D., Lefkowitz, Robert J.
The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate and desensitize agonist-occupied GPCRs. GRK2-mediated receptor phosphorylation is preceded by the agonist-dependent membrane...
Hall, Randy A., Ostedgaard, Lynda S., Premont, Richard T., Blitzer, Jeremy T., Rahman, Nadeem, Welsh, Michael J., ...
The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the β2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first...
Iaccarino, Guido, Smithwick, L. Ashley, Lefkowitz, Robert J., Koch, Walter J.
Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular...
Rockman, Howard A., Chien, Kenneth R., Choi, Dong-Ju, Iaccarino, Guido, Hunter, John J., Ross, John, ...
Heart failure is accompanied by severely impaired β-adrenergic receptor (βAR) function, which includes loss of βAR density and functional uncoupling of remaining receptors. An important mechanism...
Tang, Yuting, Hu, Liaoyuan A., Miller, William E., Ringstad, Niels, Hall, Randy A., Pitcher, Julie A., ...
Several G-protein coupled receptors, such as the β1-adrenergic receptor (β1-AR), contain polyproline motifs within their intracellular domains. Such motifs in other proteins are known to mediate...
Akhter, Shahab A., Skaer, Christine A., Kypson, Alan P., McDonald, Patricia H., Peppel, Karsten C., Glower, Donald D., ...
Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing...
Premont, Richard T., Claing, Audrey, Vitale, Nicolas, Freeman, Jennifer L. R., Pitcher, Julie A., Patton, Walter A., ...
G protein-coupled receptor activation leads to the membrane recruitment and activation of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their inactivation. We have...
White, David C., Hata, Jonathan A., Shah, Ashish S., Glower, Donald D., Lefkowitz, Robert J., Koch, Walter J.
When the heart fails, there is often a constellation of biochemical alterations of the β-adrenergic receptor (βAR) signaling system, leading to the loss of cardiac inotropic reserve. βAR...
Pierce, Kristen L., Maudsley, Stuart, Daaka, Yehia, Luttrell, Louis M., Lefkowitz, Robert J.
Acting through a number of distinct pathways, many G protein-coupled receptors (GPCRs) activate the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade....
β-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking
Kohout, Trudy A., Lin, Fang-Tsyr, Perry, Stephen J., Conner, David A., Lefkowitz, Robert J.
The two widely coexpressed isoforms of β-arrestin (termed βarrestin 1 and 2) are highly similar in amino acid sequence. The β-arrestins bind phosphorylated heptahelical receptors to desensitize...
Zhu, Wei-Zhong, Zheng, Ming, Koch, Walter J., Lefkowitz, Robert J., Kobilka, Brian K., Xiao, Rui-Ping
The goal of this study was to determine whether β1-adrenergic receptor (AR) and β2-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One...
Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds
Luttrell, Louis M., Roudabush, Francine L., Choy, Eric W., Miller, William E., Field, Michael E., Pierce, Kristen L., ...
Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of β-arrestins in the activation and targeting of extracellular signal-regulated kinase 2...
Harding, Victoria B., Jones, Larry R., Lefkowitz, Robert J., Koch, Walter J., Rockman, Howard A.
Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the...
Chen, Wei, Hu, Liaoyuan A., Semenov, Mikhail V., Yanagawa, Shinichi, Kikuchi, Akira, Lefkowitz, Robert J., ...
One aspect of the function of the β-arrestins is to serve as scaffold or adapter molecules coupling G-protein coupled receptors (GPCRs) to signal transduction pathways distinct from traditional...
Maudsley, Stuart, Zamah, A. Musa, Rahman, Nadeem, Blitzer, Jeremy T., Luttrell, Louis M., Lefkowitz, Robert J., ...
Platelet-derived growth factor (PDGF) is a potent mitogen for many cell types. The PDGF receptor (PDGFR) is a receptor tyrosine kinase that mediates the mitogenic effects of PDGF by binding to and/or...
Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice
Fong, Alan M., Premont, Richard T., Richardson, Ricardo M., Yu, Yen-Rei A., Lefkowitz, Robert J., Patel, Dhavalkumar D.
Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived...
Ahn, Seungkirl, Nelson, Christopher D., Garrison, Tiffany Runyan, Miller, William E., Lefkowitz, Robert J.
β-Arrestins bind to activated G protein-coupled receptor kinase-phosphorylated receptors, which leads to their desensitization with respect to G proteins, internalization via clathrin-coated pits,...
β-Arrestin-2 regulates the development of allergic asthma
Walker, Julia K.L., Fong, Alan M., Lawson, Barbara L., Savov, Jordan D., Patel, Dhavalkumar D., Schwartz, David A., ...
Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to...
Wei, Huijun, Ahn, Seungkirl, Shenoy, Sudha K., Karnik, Sadashiva S., Hunyady, László, Luttrell, Louis M., ...
Stimulation of a mutant angiotensin type 1A receptor (DRY/AAY) with angiotensin II (Ang II) or of a wild-type receptor with an Ang II analog ([sarcosine1,Ile4,Ile8]Ang II) fails to activate classical...
Freeman, Kalev, Lerman, Imanuel, Kranias, Evangelia G., Bohlmeyer, Teresa, Bristow, Michael R., Lefkowitz, Robert J., ...
The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative...
ACTH Receptors in the Adrenal: Specific Binding of ACTH-125I and Its Relation to Adenyl Cyclase
Lefkowitz, Robert J., Roth, Jesse, Pricer, William, Pastan, Ira
Pure monoiodo ACTH-125I was prepared that was biologically active and free of unlabeled ACTH. Extracts of adrenal cortex that contained ACTH-sensitive adenyl cyclase, bound ACTH-125I; extracts that...
Baillie, George S., Sood, Arvind, McPhee, Ian, Gall, Irene, Perry, Stephen J., Lefkowitz, Robert J., ...
Phosphorylation of the β2 adrenoreceptor (β2AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (Gs) to inhibitory...
Affinity chromatography of human platelet α2-adrenergic receptors
Regan, John W., Barden, Nicholas, Lefkowitz, Robert J., Caron, Marc G., DeMarinis, Robert M., Krog, Arnold J., ...
Catecholamines, such as epinephrine, inhibit the enzyme adenylate cyclase (EC 4.6.1.1) via a specific receptor mechanism involving α2-adrenergic receptors. In order to facilitate purification of...
Pharmacological Characterizations of Adrenergic Receptors in Human Adipocytes
Burns, Thomas W., Langley, Paul E., Terry, Boyd E., Bylund, David B., Hoffman, Brian B., Tharp, Michael D., ...
Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the...
Identification of α-Adrenergic Receptors in Human Platelets by [3H]Dihydroergocryptine Binding
Newman, Kurt D., Williams, Lewis T., Bishopric, N. Hahr, Lefkowitz, Robert J.
Binding of [3H]dihydroergocryptine to platelet lysates appears to have all the characteristics of binding to α-adrenergic receptors. At 25°C binding reaches equilibrium within 20 min and is...
Antibodies raised against purified β-adrenergic receptors specifically bind β-adrenergic ligands
Caron, Marc G., Srinivasan, Yogambal, Snyderman, Ralph, Lefkowitz, Robert J.
Antibodies raised against purified β-adrenergic receptors themselves specifically bind β-adrenergic ligands. Digitonin-solubilized frog (Rana pipiens) erythrocyte β-adrenergic receptors, purified...
Lefkowitz, Robert J., Haber, Edgar
The 78,000 × g microsomal fraction of canine ventricular myocardium effected a 20-fold concentration of [3H]norepinephrine from a 10-9 M solution. The [3H]norepinephrine bound was displaced by...
Lefkowitz, Robert J., Haber, Edgar, O'Hara, Donald
A protein that binds catecholamines with a specificity parallel to that of their in vivo effects on cardiac contractility (isoproterenol > epinephrine or norepinephrine > dopamine >...
Anti–β1-adrenergic receptor antibodies and heart failure: causation, not just correlation
Freedman, Neil J., Lefkowitz, Robert J.
Antibodies specific for the β1-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these...
Maurice, John P., Hata, Jonathan A., Shah, Ashish S., White, David C., McDonald, Patricia H., Dolber, Paul C., ...
Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy...
Agonist-induced increase in apparent β-adrenergic receptor size
Limbird, Lee E., Lefkowitz, Robert J.
The properties of digitonin-solubilized β-adrenergic receptors from frog erythrocyte membranes were studied by gel exclusion chromatography on AcA 34 Ultragel. β-Adrenergic receptor binding...
β-Arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα
Witherow, D. Scott, Garrison, Tiffany Runyan, Miller, William E., Lefkowitz, Robert J.
In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, β-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor...
Davies, Albert O., Lefkowitz, Robert J.
The receptor alterations involved in catecholamine-induced desensitization of adenylate cyclase in human neutrophils have been investigated as has the ability of hydrocortisone to modify such...
The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels
Dinudom, Anuwat, Fotia, Andrew B., Lefkowitz, Robert J., Young, John A., Kumar, Sharad, Cook, David I.
Epithelial Na+ channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases,...
Usui, Isao, Imamura, Takeshi, Huang, Jie, Satoh, Hiroaki, Shenoy, Sudha K., Lefkowitz, Robert J., ...
β-Arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous...
Kim, Jihee, Ahn, Seungkirl, Ren, Xiu-Rong, Whalen, Erin J., Reiter, Eric, Wei, Huijun, ...
β-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor...
Ren, Xiu-Rong, Reiter, Eric, Ahn, Seungkirl, Kim, Jihee, Chen, Wei, Lefkowitz, Robert J.
Signaling through β-arrestins is a recently appreciated mechanism used by seven-transmembrane receptors. Because G protein-coupled receptor kinase (GRK) phosphorylation of such receptors is...
Shenoy, Sudha K, Lefkowitz, Robert J
Beta-arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated...
When 7 transmembrane receptors are not G protein–coupled receptors
Rajagopal, Keshava, Lefkowitz, Robert J., Rockman, Howard A.
Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal...
Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity
Claing, Audrey, Perry, Stephen J., Achiriloaie, Mircea, Walker, Julia K. L., Albanesi, Joseph P., Lefkowitz, Robert J., ...
Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1. This protein initially was identified as an interacting...
Receptor and Gβγ isoform-specific interactions with G protein-coupled receptor kinases
Daaka, Yehia, Pitcher, Julie A., Richardson, Mark, Stoffel, Robert H., Robishaw, Janet D., Lefkowitz, Robert J.
The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate and desensitize agonist-occupied GPCRs. GRK2-mediated receptor phosphorylation is preceded by the agonist-dependent membrane...
Hall, Randy A., Ostedgaard, Lynda S., Premont, Richard T., Blitzer, Jeremy T., Rahman, Nadeem, Welsh, Michael J., ...
The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the β2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first...
Iaccarino, Guido, Smithwick, L. Ashley, Lefkowitz, Robert J., Koch, Walter J.
Restenosis continues to be a major problem limiting the effectiveness of revascularization procedures. To date, the roles of heterotrimeric G proteins in the triggering of pathological vascular...
Rockman, Howard A., Chien, Kenneth R., Choi, Dong-Ju, Iaccarino, Guido, Hunter, John J., Ross, John, ...
Heart failure is accompanied by severely impaired β-adrenergic receptor (βAR) function, which includes loss of βAR density and functional uncoupling of remaining receptors. An important mechanism...
Tang, Yuting, Hu, Liaoyuan A., Miller, William E., Ringstad, Niels, Hall, Randy A., Pitcher, Julie A., ...
Several G-protein coupled receptors, such as the β1-adrenergic receptor (β1-AR), contain polyproline motifs within their intracellular domains. Such motifs in other proteins are known to mediate...
Akhter, Shahab A., Skaer, Christine A., Kypson, Alan P., McDonald, Patricia H., Peppel, Karsten C., Glower, Donald D., ...
Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing...
Premont, Richard T., Claing, Audrey, Vitale, Nicolas, Freeman, Jennifer L. R., Pitcher, Julie A., Patton, Walter A., ...
G protein-coupled receptor activation leads to the membrane recruitment and activation of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their inactivation. We have...
White, David C., Hata, Jonathan A., Shah, Ashish S., Glower, Donald D., Lefkowitz, Robert J., Koch, Walter J.
When the heart fails, there is often a constellation of biochemical alterations of the β-adrenergic receptor (βAR) signaling system, leading to the loss of cardiac inotropic reserve. βAR...
Pierce, Kristen L., Maudsley, Stuart, Daaka, Yehia, Luttrell, Louis M., Lefkowitz, Robert J.
Acting through a number of distinct pathways, many G protein-coupled receptors (GPCRs) activate the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade....
β-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking
Kohout, Trudy A., Lin, Fang-Tsyr, Perry, Stephen J., Conner, David A., Lefkowitz, Robert J.
The two widely coexpressed isoforms of β-arrestin (termed βarrestin 1 and 2) are highly similar in amino acid sequence. The β-arrestins bind phosphorylated heptahelical receptors to desensitize...
Zhu, Wei-Zhong, Zheng, Ming, Koch, Walter J., Lefkowitz, Robert J., Kobilka, Brian K., Xiao, Rui-Ping
The goal of this study was to determine whether β1-adrenergic receptor (AR) and β2-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One...
Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds
Luttrell, Louis M., Roudabush, Francine L., Choy, Eric W., Miller, William E., Field, Michael E., Pierce, Kristen L., ...
Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of β-arrestins in the activation and targeting of extracellular signal-regulated kinase 2...
Harding, Victoria B., Jones, Larry R., Lefkowitz, Robert J., Koch, Walter J., Rockman, Howard A.
Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the...
Chen, Wei, Hu, Liaoyuan A., Semenov, Mikhail V., Yanagawa, Shinichi, Kikuchi, Akira, Lefkowitz, Robert J., ...
One aspect of the function of the β-arrestins is to serve as scaffold or adapter molecules coupling G-protein coupled receptors (GPCRs) to signal transduction pathways distinct from traditional...
Maudsley, Stuart, Zamah, A. Musa, Rahman, Nadeem, Blitzer, Jeremy T., Luttrell, Louis M., Lefkowitz, Robert J., ...
Platelet-derived growth factor (PDGF) is a potent mitogen for many cell types. The PDGF receptor (PDGFR) is a receptor tyrosine kinase that mediates the mitogenic effects of PDGF by binding to and/or...
Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice
Fong, Alan M., Premont, Richard T., Richardson, Ricardo M., Yu, Yen-Rei A., Lefkowitz, Robert J., Patel, Dhavalkumar D.
Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived...
Ahn, Seungkirl, Nelson, Christopher D., Garrison, Tiffany Runyan, Miller, William E., Lefkowitz, Robert J.
β-Arrestins bind to activated G protein-coupled receptor kinase-phosphorylated receptors, which leads to their desensitization with respect to G proteins, internalization via clathrin-coated pits,...
β-Arrestin-2 regulates the development of allergic asthma
Walker, Julia K.L., Fong, Alan M., Lawson, Barbara L., Savov, Jordan D., Patel, Dhavalkumar D., Schwartz, David A., ...
Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to...
Wei, Huijun, Ahn, Seungkirl, Shenoy, Sudha K., Karnik, Sadashiva S., Hunyady, László, Luttrell, Louis M., ...
Stimulation of a mutant angiotensin type 1A receptor (DRY/AAY) with angiotensin II (Ang II) or of a wild-type receptor with an Ang II analog ([sarcosine1,Ile4,Ile8]Ang II) fails to activate classical...
Freeman, Kalev, Lerman, Imanuel, Kranias, Evangelia G., Bohlmeyer, Teresa, Bristow, Michael R., Lefkowitz, Robert J., ...
The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative...
ACTH Receptors in the Adrenal: Specific Binding of ACTH-125I and Its Relation to Adenyl Cyclase
Lefkowitz, Robert J., Roth, Jesse, Pricer, William, Pastan, Ira
Pure monoiodo ACTH-125I was prepared that was biologically active and free of unlabeled ACTH. Extracts of adrenal cortex that contained ACTH-sensitive adenyl cyclase, bound ACTH-125I; extracts that...
Baillie, George S., Sood, Arvind, McPhee, Ian, Gall, Irene, Perry, Stephen J., Lefkowitz, Robert J., ...
Phosphorylation of the β2 adrenoreceptor (β2AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (Gs) to inhibitory...
Affinity chromatography of human platelet α2-adrenergic receptors
Regan, John W., Barden, Nicholas, Lefkowitz, Robert J., Caron, Marc G., DeMarinis, Robert M., Krog, Arnold J., ...
Catecholamines, such as epinephrine, inhibit the enzyme adenylate cyclase (EC 4.6.1.1) via a specific receptor mechanism involving α2-adrenergic receptors. In order to facilitate purification of...
Pharmacological Characterizations of Adrenergic Receptors in Human Adipocytes
Burns, Thomas W., Langley, Paul E., Terry, Boyd E., Bylund, David B., Hoffman, Brian B., Tharp, Michael D., ...
Three types of adrenergic receptors, beta, alpha-1, and alpha-2, were identified in human adipocytes, isolated from properitoneal adipose tissue, using both the binding of radioactive ligands and the...
Identification of α-Adrenergic Receptors in Human Platelets by [3H]Dihydroergocryptine Binding
Newman, Kurt D., Williams, Lewis T., Bishopric, N. Hahr, Lefkowitz, Robert J.
Binding of [3H]dihydroergocryptine to platelet lysates appears to have all the characteristics of binding to α-adrenergic receptors. At 25°C binding reaches equilibrium within 20 min and is...
Antibodies raised against purified β-adrenergic receptors specifically bind β-adrenergic ligands
Caron, Marc G., Srinivasan, Yogambal, Snyderman, Ralph, Lefkowitz, Robert J.
Antibodies raised against purified β-adrenergic receptors themselves specifically bind β-adrenergic ligands. Digitonin-solubilized frog (Rana pipiens) erythrocyte β-adrenergic receptors, purified...
Lefkowitz, Robert J., Haber, Edgar
The 78,000 × g microsomal fraction of canine ventricular myocardium effected a 20-fold concentration of [3H]norepinephrine from a 10-9 M solution. The [3H]norepinephrine bound was displaced by...
Lefkowitz, Robert J., Haber, Edgar, O'Hara, Donald
A protein that binds catecholamines with a specificity parallel to that of their in vivo effects on cardiac contractility (isoproterenol > epinephrine or norepinephrine > dopamine >...
Anti–β1-adrenergic receptor antibodies and heart failure: causation, not just correlation
Freedman, Neil J., Lefkowitz, Robert J.
Antibodies specific for the β1-adrenergic receptor are found in patients with chronic heart failure of various etiologies. From work presented in this issue of the JCI, we can now infer that these...
Maurice, John P., Hata, Jonathan A., Shah, Ashish S., White, David C., McDonald, Patricia H., Dolber, Paul C., ...
Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy...
Agonist-induced increase in apparent β-adrenergic receptor size
Limbird, Lee E., Lefkowitz, Robert J.
The properties of digitonin-solubilized β-adrenergic receptors from frog erythrocyte membranes were studied by gel exclusion chromatography on AcA 34 Ultragel. β-Adrenergic receptor binding...
β-Arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα
Witherow, D. Scott, Garrison, Tiffany Runyan, Miller, William E., Lefkowitz, Robert J.
In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, β-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor...
Davies, Albert O., Lefkowitz, Robert J.
The receptor alterations involved in catecholamine-induced desensitization of adenylate cyclase in human neutrophils have been investigated as has the ability of hydrocortisone to modify such...
The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels
Dinudom, Anuwat, Fotia, Andrew B., Lefkowitz, Robert J., Young, John A., Kumar, Sharad, Cook, David I.
Epithelial Na+ channels mediate the transport of Na across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases,...
Usui, Isao, Imamura, Takeshi, Huang, Jie, Satoh, Hiroaki, Shenoy, Sudha K., Lefkowitz, Robert J., ...
β-Arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous...
Kim, Jihee, Ahn, Seungkirl, Ren, Xiu-Rong, Whalen, Erin J., Reiter, Eric, Wei, Huijun, ...
β-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor...
Ren, Xiu-Rong, Reiter, Eric, Ahn, Seungkirl, Kim, Jihee, Chen, Wei, Lefkowitz, Robert J.
Signaling through β-arrestins is a recently appreciated mechanism used by seven-transmembrane receptors. Because G protein-coupled receptor kinase (GRK) phosphorylation of such receptors is...
Shenoy, Sudha K, Lefkowitz, Robert J
Beta-arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated...
When 7 transmembrane receptors are not G protein–coupled receptors
Rajagopal, Keshava, Lefkowitz, Robert J., Rockman, Howard A.
Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal...
Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2▿
Meloni, Alison R., Fralish, Gregory B., Kelly, Patrick, Salahpour, Ali, Chen, James K., Wechsler-Reya, Robert J., ...
Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular...
Rajagopal, Keshava, Whalen, Erin J., Violin, Jonathan D., Stiber, Jonathan A., Rosenberg, Paul B., Premont, Richard T., ...
The G protein-coupled receptor kinases (GRKs) and β-arrestins, families of molecules essential to the desensitization of G protein-dependent signaling via seven-transmembrane receptors (7TMRs), have...
β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection
Noma, Takahisa, Lemaire, Anthony, Naga Prasad, Sathyamangla V., Barki-Harrington, Liza, Tilley, Douglas G., Chen, Juhsien, ...
Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent...
G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal
Terman, Gregory W, Jin, Wenzhen, Cheong, Young-Pyo, Lowe, Janet, Caron, Marc G, Lefkowitz, Robert J, ...
Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged...
Functional specialization of β-arrestin interactions revealed by proteomic analysis
Xiao, Kunhong, McClatchy, Daniel B., Shukla, Arun K., Zhao, Yang, Chen, Minyong, Shenoy, Sudha K., ...
β-arrestins are cytosolic proteins that form complexes with seven-transmembrane receptors after agonist stimulation and phosphorylation by the G protein-coupled receptor kinases. They play an...
The annual ASCI meeting: does nostalgia have a future?
For many academic physician-scientists, the yearly Tri-Societies meeting of the ASCI, AAP, and AFCR during the 1960s, ’70s, and ’80s was an annual rite of spring and the focal point of the...
A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling
Wisler, James W., DeWire, Scott M., Whalen, Erin J., Violin, Jonathan D., Drake, Matthew T., Ahn, Seungkirl, ...
For many years, β-adrenergic receptor antagonists (β-blockers or βAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial...
Distinct conformational changes in β-arrestin report biased agonism at seven-transmembrane receptors
Shukla, Arun K., Violin, Jonathan D., Whalen, Erin J., Gesty-Palmer, Diane, Shenoy, Sudha K., Lefkowitz, Robert J.
β-arrestins critically regulate G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), both by inhibiting classical G protein signaling and by initiating distinct...
β-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation*S⃞
Ahn, Seungkirl, Kim, Jihee, Hara, Makoto R., Ren, Xiu-Rong, Lefkowitz, Robert J.
β-Arrestins, originally discovered as terminators of G protein-coupled receptor signaling, have more recently been appreciated to also function as signal transducers in their own right, although the...
β-Arrestin-mediated Signaling Regulates Protein Synthesis*S⃞
DeWire, Scott M., Kim, Jihee, Whalen, Erin J., Ahn, Seungkirl, Chen, Minyong, Lefkowitz, Robert J.
Seven transmembrane receptors (7TMRs) exert strong regulatory influences on virtually all physiological processes. Although it is historically assumed that heterotrimeric G proteins mediate these...
Kim, Jihee, Ahn, Seungkirl, Rajagopal, Keshava, Lefkowitz, Robert J.
Recent studies in receptor-transfected cell lines have demonstrated that extracellular signal-regulated kinase (ERK) activation by angiotensin type 1A receptor and other G protein-coupled receptors...
β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice
Walters, Robert W., Shukla, Arun K., Kovacs, Jeffrey J., Violin, Jonathan D., DeWire, Scott M., Lam, Christopher M., ...
Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic...
Shenoy, Sudha K., Modi, Aalok S., Shukla, Arun K., Xiao, Kunhong, Berthouze, Magali, Ahn, Seungkirl, ...
β-Arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination...
Zidar, David A., Violin, Jonathan D., Whalen, Erin J., Lefkowitz, Robert J.
CCL19 and CCL21 are endogenous agonists for the seven-transmembrane receptor CCR7. They are equally active in promoting G protein stimulation and chemotaxis. Yet, we find that they result in striking...
Nelson, Christopher D., Kovacs, Jeffery J., Nobles, Kelly N., Whalen, Erin J., Lefkowitz, Robert J.
Members of the seven-transmembrane receptor (7TMR) superfamily are sequestered from the plasma membrane following stimulation both to limit cellular responses as well as to initiate novel G...