Neil Jonathan Freedman
Professor of Medicine
Our work focuses on atherosclerosis-related signal transduction and the genetic bases of atherosclerosis and vein graft failure, both in vitro and in vivo. We investigate the regulation of receptor protein tyrosine kinases by G protein-coupled receptor kinases (GRKs), and the role of GRKs and β-arrestins in atherosclerosis; the role of tumor necrosis factor and its receptors in atherosclerosis; and the role of the dual Rho-GEF kalirin in atherosclerosis. For in vivo modeling of atherosclerosis and neointimal hyperplasia, we use mouse carotid artery bypass grafting with either veins or arteries from gene-deleted or congenic wild type mice, as well as aortic atherosclerosis studies and bone marrow transplantation. To study receptor phosphorylation, signal transduction, and intracellular trafficking, we employ primary smooth muscle cells, endothelial cells, and macrophages derived from knockout mice or treated with RNA interference.
Key Words: atherosclerosis, G protein-coupled receptor kinases, arrestins, desensitization, phosphorylation, platelet-derived growth factor receptors, receptor protein tyrosine kinases, smooth muscle cells, neointimal hyperplasia, Rho-GEF.
Key Words: atherosclerosis, G protein-coupled receptor kinases, arrestins, desensitization, phosphorylation, platelet-derived growth factor receptors, receptor protein tyrosine kinases, smooth muscle cells, neointimal hyperplasia, Rho-GEF.
Current Appointments & Affiliations
- Professor of Medicine, Medicine, Cardiology, Medicine 2017
- Professor in Cell Biology, Cell Biology, Basic Science Departments 2017
Contact Information
- 447 Clin & Res Labs, Box 102150 Duke University Medical Ctr, Durham, NC 27710
- Duke Box 102150, Durham, NC 27710
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neil.freedman@duke.edu
(919) 681-6461
- Background
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Education, Training, & Certifications
- Fellow in Cardiology, Medicine, Duke University 1990 - 1993
- Visiting Scientist, Massachusetts Institute of Technology 1989 - 1990
- Research Fellow in Medicine, Medicine, Brigham and Women's Hospital 1988 - 1989
- Medical Resident, Medicine, Beth Israel Deaconess Medical Center 1985 - 1988
- M.D., Harvard University 1985
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Previous Appointments & Affiliations
- Assistant Professor in Cell Biology, Cell Biology, Basic Science Departments 2005 - 2017
- Associate Professor of Medicine, Medicine, Cardiology, Medicine 2006 - 2017
- Assistant Professor of Medicine, Medicine, Cardiology, Medicine 1996 - 2006
- Associate in the Department of Medicine, Medicine, Cardiology, Medicine 1993 - 1996
- Research
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Selected Grants
- Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis awarded by National Institutes of Health 2022 - 2026
- Mechanisms Regulating Vascular Homeostasis awarded by National Institutes of Health 2021 - 2025
- Anti-Atherogenic Mechanisms of Drebrin awarded by National Institutes of Health 2019 - 2023
- Multidisciplinary Heart and Vascular Diseases awarded by National Institutes of Health 1975 - 2023
- Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20 awarded by National Institutes of Health 2019 - 2023
- Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation awarded by National Institutes of Health 2017 - 2021
- Role of Debrin in Vascular Smooth Muscle Transdifferentiation awarded by American Heart Association 2019
- Role of Drebrin in Atherosclerosis awarded by National Institutes of Health 2014 - 2019
- Anti-atherogenic Mechanisms of the Dual Rho-GEF Kalirin awarded by National Institutes of Health 2014 - 2018
- Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20 awarded by National Institutes of Health 2014 - 2018
- Role of Drebrin in Vascular Smooth Muscle Remodeling awarded by National Institutes of Health 2013 - 2018
- Desensitization of Vascular Receptor Tyrosine Kinases awarded by National Institutes of Health 2005 - 2012
- Mechanisms of Arterial Wall-Mediated Atherogenesis awarded by National Institutes of Health 2005 - 2009
- Aging, Atherosclerosis, and the Arterial Wall awarded by National Institutes of Health 2006 - 2009
- Inflammation in Vein Graft Disease: A Genetic Approach awarded by National Institutes of Health 2004 - 2006
- TNF-Inhibitor Gene Therapy for Neointimal Hyperplasia awarded by National Institutes of Health 2001 - 2005
- Receptor Kinase Gene Therapy for Neointimal Hyperplasia awarded by National Institutes of Health 1999 - 2004
- Same awarded by Department of Health and Human Services 1997 - 2001
- Receptor Kinase Gene Therapy For Neointimal Hyperplasia awarded by National Institutes of Health 1997 - 1999
- Receptor Desensitization In The Cardiovascular System awarded by National Institutes of Health 1994 - 1999
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External Relationships
- Faiella & Gulden, P.A.
- Publications & Artistic Works
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Selected Publications
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Academic Articles
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Freedman, Neil J. “From Colon to Aortic Aneurysm: Trek of the Treg.” Jacc Basic Transl Sci, vol. 7, no. 9, Sept. 2022, pp. 948–50. Pubmed, doi:10.1016/j.jacbts.2022.07.003.Full Text Link to Item
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Wu, Jiao-Hui, et al. “Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.” Cardiovasc Res, vol. 118, no. 3, Feb. 2022, pp. 772–84. Pubmed, doi:10.1093/cvr/cvab156.Full Text Open Access Copy Link to Item
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Zhang, Lisheng, et al. “Drebrin regulates angiotensin II-induced aortic remodelling.” Cardiovasc Res, vol. 114, no. 13, Nov. 2018, pp. 1806–15. Pubmed, doi:10.1093/cvr/cvy151.Full Text Link to Item
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Jean-Charles, Pierre-Yves, et al. “USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis.” Arterioscler Thromb Vasc Biol, vol. 38, no. 10, Oct. 2018, pp. 2295–305. Pubmed, doi:10.1161/ATVBAHA.118.311071.Full Text Link to Item
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Freedman, Neil J., and Sudha K. Shenoy. “Regulation of inflammation by β-arrestins: Not just receptor tales.” Cell Signal, vol. 41, Jan. 2018, pp. 41–45. Pubmed, doi:10.1016/j.cellsig.2017.02.008.Full Text Link to Item
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Zhang, Lisheng, et al. “Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.” Cardiovasc Res, vol. 113, no. 13, Nov. 2017, pp. 1551–59. Pubmed, doi:10.1093/cvr/cvx177.Full Text Open Access Copy Link to Item
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Smith, Jeffrey S., et al. “C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways.” Mol Pharmacol, vol. 92, no. 2, Aug. 2017, pp. 136–50. Pubmed, doi:10.1124/mol.117.108522.Full Text Link to Item
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Stiber, Jonathan A., et al. “The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia.” Arterioscler Thromb Vasc Biol, vol. 36, no. 5, May 2016, pp. 984–93. Pubmed, doi:10.1161/ATVBAHA.115.306140.Full Text Link to Item
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Jean-Charles, Pierre-Yves, et al. “Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of β-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor κB (NFκB) Activation.” J Biol Chem, vol. 291, no. 14, Apr. 2016, pp. 7450–64. Pubmed, doi:10.1074/jbc.M115.687129.Full Text Link to Item
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Jean-Charles, P. .. Y., et al. “Chapter Nine - Cellular Roles of Beta-Arrestins as Substrates and Adaptors of Ubiquitination and Deubiquitination.” Prog Mol Biol Transl Sci, vol. 141, 2016, pp. 339–69. Pubmed, doi:10.1016/bs.pmbts.2016.04.003.Full Text Link to Item
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Lu, Yuan, et al. “Kruppel-like factor 15 is critical for vascular inflammation.” J Clin Invest, vol. 123, no. 10, Oct. 2013, pp. 4232–41. Pubmed, doi:10.1172/JCI68552.Full Text Link to Item
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Chandra, Rashmi, et al. “Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion.” J Clin Invest, vol. 123, no. 8, Aug. 2013, pp. 3343–52. Pubmed, doi:10.1172/JCI68587.Full Text Link to Item
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Wu, Jiao-Hui, et al. “Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.” Arterioscler Thromb Vasc Biol, vol. 33, no. 4, Apr. 2013, pp. 702–08. Pubmed, doi:10.1161/ATVBAHA.112.300234.Full Text Link to Item
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Han, Sang-oh, et al. “MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.” J Cell Biol, vol. 199, no. 5, Nov. 2012, pp. 817–30. Pubmed, doi:10.1083/jcb.201208192.Full Text Link to Item
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Zhang, Lisheng, et al. “Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells.” J Vasc Surg, vol. 56, no. 5, Nov. 2012, pp. 1390–97. Pubmed, doi:10.1016/j.jvs.2012.03.254.Full Text Link to Item
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Wu, Jiao-Hui, et al. “G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.” Arterioscler Thromb Vasc Biol, vol. 32, no. 2, Feb. 2012, pp. 308–16. Pubmed, doi:10.1161/ATVBAHA.111.239608.Full Text Link to Item
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Brown, Melissa A., et al. “Human umbilical cord blood-derived endothelial cells reendothelialize vein grafts and prevent thrombosis.” Arterioscler Thromb Vasc Biol, vol. 30, no. 11, Nov. 2010, pp. 2150–55. Pubmed, doi:10.1161/ATVBAHA.110.207076.Full Text Link to Item
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Zhu, Shoukang, et al. “Human umbilical cord blood endothelial progenitor cells decrease vein graft neointimal hyperplasia in SCID mice.” Atherosclerosis, vol. 212, no. 1, Sept. 2010, pp. 63–69. Pubmed, doi:10.1016/j.atherosclerosis.2010.04.018.Full Text Link to Item
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Zhang, Lisheng, et al. “Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies.” Hum Mol Genet, vol. 19, no. 14, July 2010, pp. 2754–66. Pubmed, doi:10.1093/hmg/ddq172.Full Text Link to Item
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Cai, Xinjiang, et al. “Reciprocal regulation of the platelet-derived growth factor receptor-beta and G protein-coupled receptor kinase 5 by cross-phosphorylation: effects on catalysis.” Mol Pharmacol, vol. 75, no. 3, Mar. 2009, pp. 626–36. Pubmed, doi:10.1124/mol.108.050278.Full Text Link to Item
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Shah, Svati H., et al. “Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.” Plos Genet, vol. 5, no. 1, Jan. 2009, p. e1000318. Pubmed, doi:10.1371/journal.pgen.1000318.Full Text Open Access Copy Link to Item
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Shenoy, Sudha K., et al. “Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor.” J Biol Chem, vol. 283, no. 32, Aug. 2008, pp. 22166–76. Pubmed, doi:10.1074/jbc.M709668200.Full Text Link to Item
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Kim, Jihee, et al. “Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.” Circ Res, vol. 103, no. 1, July 2008, pp. 70–79. Pubmed, doi:10.1161/CIRCRESAHA.108.172338.Full Text Open Access Copy Link to Item
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Wang, L., et al. “Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease.” Ann Hum Genet, vol. 72, no. Pt 4, July 2008, pp. 443–53. Pubmed, doi:10.1111/j.1469-1809.2008.00433.x.Full Text Link to Item
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Zhang, Lisheng, et al. “Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery.” Arterioscler Thromb Vasc Biol, vol. 28, no. 2, Feb. 2008, pp. 284–89. Pubmed, doi:10.1161/ATVBAHA.107.151613.Full Text Link to Item
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Vinge, Leif Erik, et al. “Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function.” Mol Pharmacol, vol. 72, no. 3, Sept. 2007, pp. 582–91. Pubmed, doi:10.1124/mol.107.035766.Full Text Link to Item
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Zhang, Lisheng, et al. “Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis.” Arterioscler Thromb Vasc Biol, vol. 27, no. 5, May 2007, pp. 1087–94. Pubmed, doi:10.1161/ATVBAHA.0000261548.49790.63.Full Text Link to Item
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Wu, Jiao-Hui, et al. “Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2.” J Biol Chem, vol. 281, no. 49, Dec. 2006, pp. 37758–72. Pubmed, doi:10.1074/jbc.M605756200.Full Text Link to Item
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Freedman, Neil J., and Geoffrey S. Ginsburg. “Novel--and "neu"--therapeutic possibilities for heart failure.” J Am Coll Cardiol, vol. 48, no. 7, Oct. 2006, pp. 1448–50. Pubmed, doi:10.1016/j.jacc.2006.07.005.Full Text Link to Item
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Cai, Xinjiang, and Neil J. Freedman. “New therapeutic possibilities for vein graft disease in the post-edifoligide era.” Future Cardiol, vol. 2, no. 4, July 2006, pp. 493–501. Pubmed, doi:10.2217/14796678.2.4.493.Full Text Link to Item
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Wu, Jiao-Hui, et al. “The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition.” J Biol Chem, vol. 280, no. 35, Sept. 2005, pp. 31027–35. Pubmed, doi:10.1074/jbc.M501473200.Full Text Link to Item
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Peppel, Karsten, et al. “Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms.” Cardiovasc Res, vol. 65, no. 3, Feb. 2005, pp. 674–82. Pubmed, doi:10.1016/j.cardiores.2004.10.031.Full Text Link to Item
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Zhang, Lisheng, et al. “Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells.” Arterioscler Thromb Vasc Biol, vol. 24, no. 12, Dec. 2004, pp. 2277–83. Pubmed, doi:10.1161/01.ATV.0000147766.68987.0d.Full Text Link to Item
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Hildreth, Kerry L., et al. “Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor.” J Biol Chem, vol. 279, no. 40, Oct. 2004, pp. 41775–82. Pubmed, doi:10.1074/jbc.M403274200.Full Text Link to Item
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Freedman, Neil J., and Robert J. Lefkowitz. “Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.” J Clin Invest, vol. 113, no. 10, May 2004, pp. 1379–82. Pubmed, doi:10.1172/JCI21748.Full Text Open Access Copy Link to Item
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Zhang, Lisheng, et al. “Graft-extrinsic cells predominate in vein graft arterialization.” Arterioscler Thromb Vasc Biol, vol. 24, no. 3, Mar. 2004, pp. 470–76. Pubmed, doi:10.1161/01.ATV.0000116865.98067.31.Full Text Link to Item
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Wu, Jiao-Hui, et al. “The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor.” J Biol Chem, vol. 278, no. 45, Nov. 2003, pp. 44238–45. Pubmed, doi:10.1074/jbc.M309450200.Full Text Link to Item
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Freedman, Neil J., et al. “Phosphorylation of the platelet-derived growth factor receptor-beta and epidermal growth factor receptor by G protein-coupled receptor kinase-2. Mechanisms for selectivity of desensitization.” J Biol Chem, vol. 277, no. 50, Dec. 2002, pp. 48261–69. Pubmed, doi:10.1074/jbc.M204431200.Full Text Link to Item
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Peppel, Karsten, et al. “Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells reduces neointimal hyperplasia.” J Mol Cell Cardiol, vol. 34, no. 10, Oct. 2002, pp. 1399–409. Pubmed, doi:10.1006/jmcc.2002.2092.Full Text Link to Item
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Zhang, Lisheng, et al. “Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model.” J Vasc Surg, vol. 36, no. 4, Oct. 2002, pp. 824–32.Link to Item
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Liang, M., et al. “Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.” Biochemistry, vol. 40, no. 49, Dec. 2001, pp. 15031–37. Pubmed, doi:10.1021/bi011453z.Full Text Link to Item
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Peppel, K., et al. “Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors.” Circulation, vol. 102, no. 7, Aug. 2000, pp. 793–99. Pubmed, doi:10.1161/01.cir.102.7.793.Full Text Link to Item
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Pitcher, J. A., et al. “G protein-coupled receptor kinases.” Annu Rev Biochem, vol. 67, 1998, pp. 653–92. Pubmed, doi:10.1146/annurev.biochem.67.1.653.Full Text Link to Item
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Freedman, N. J., et al. “Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity.” J Biol Chem, vol. 272, no. 28, July 1997, pp. 17734–43. Pubmed, doi:10.1074/jbc.272.28.17734.Full Text Link to Item
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Oppermann, M., et al. “Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases.” Proc Natl Acad Sci U S A, vol. 93, no. 15, July 1996, pp. 7649–54. Pubmed, doi:10.1073/pnas.93.15.7649.Full Text Open Access Copy Link to Item
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Oppermann, M., et al. “Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.” J Biol Chem, vol. 271, no. 22, May 1996, pp. 13266–72. Pubmed, doi:10.1074/jbc.271.22.13266.Full Text Link to Item
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Freedman, N. J., and R. J. Lefkowitz. “Desensitization of G protein-coupled receptors.” Recent Prog Horm Res, vol. 51, 1996, pp. 319–51.Link to Item
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Pei, G., et al. “Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C.” Mol Pharmacol, vol. 48, no. 2, Aug. 1995, pp. 173–77.Link to Item
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Freedman, N. J., et al. “Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase.” J Biol Chem, vol. 270, no. 30, July 1995, pp. 17953–61. Pubmed, doi:10.1074/jbc.270.30.17953.Full Text Link to Item
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Barak, L. S., et al. “A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.” J Biol Chem, vol. 269, no. 4, Jan. 1994, pp. 2790–95.Link to Item
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Ishii, K., et al. “Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases.” J Biol Chem, vol. 269, no. 2, Jan. 1994, pp. 1125–30.Link to Item
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Inglese, J., et al. “Structure and mechanism of the G protein-coupled receptor kinases.” J Biol Chem, vol. 268, no. 32, Nov. 1993, pp. 23735–38.Link to Item
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Freedman, S. F., et al. “Effects of ocular carteolol and timolol on plasma high-density lipoprotein cholesterol level.” Am J Ophthalmol, vol. 116, no. 5, Nov. 1993, pp. 600–11. Pubmed, doi:10.1016/s0002-9394(14)73203-9.Full Text Link to Item
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Liggett, S. B., et al. “Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.” Proc Natl Acad Sci U S A, vol. 90, no. 8, Apr. 1993, pp. 3665–69. Pubmed, doi:10.1073/pnas.90.8.3665.Full Text Open Access Copy Link to Item
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Resnick, D., et al. “Secreted extracellular domains of macrophage scavenger receptors form elongated trimers which specifically bind crocidolite asbestos.” J Biol Chem, vol. 268, no. 5, Feb. 1993, pp. 3538–45.Link to Item
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Penman, M., et al. “The type I and type II bovine scavenger receptors expressed in Chinese hamster ovary cells are trimeric proteins with collagenous triple helical domains comprising noncovalently associated monomers and Cys83-disulfide-linked dimers.” J Biol Chem, vol. 266, no. 35, Dec. 1991, pp. 23985–93.Link to Item
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Freeman, M., et al. “Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein.” Proc Natl Acad Sci U S A, vol. 88, no. 11, June 1991, pp. 4931–35. Pubmed, doi:10.1073/pnas.88.11.4931.Full Text Link to Item
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Newrock, Kenneth M., et al. “Isolation of sea urchin embryo histone H2Aα1 and immunological identification of other stage-specific H2A proteins.” Developmental Biology, vol. 89, no. 1, Elsevier BV, Jan. 1982, pp. 248–53. Crossref, doi:10.1016/0012-1606(82)90311-6.Full Text
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