Biomedical Research Education & Training
Faculty Member

Breyer, Richard M., Ph.D.
Professor of Medicine
Professor of Biochemistry
Ruth King Scoville Chair in Medicine
Professor of Pharmacology

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Phone Number: 615-343-0257

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Breyer, Richard's picture
Academic history
B.S., Michigan
M.S., Massachusetts Inst Tech
Ph.D., Massachusetts Inst Tech

Office Address   Mailing Address

B-3214A Medical Center North

S-3223 MCN 2372

Research Keywords
Prostaglandin GPCR knockout physiology, Biochemistry, Cancer, Fertility, Immunology, Kidney, Membrane, Pharmacology, Pulmonary, Receptor, Renal biology, Reproduction, Signal transduction, Structural Biology

Research Specialty
Structure, Function and Biology of Prostanoid Receptors

Research Description
Prostaglandin E2 (PGE2) mediates a wide range of biological effects including anti-inflammatory effects,airway resistance in asthma, fertility and maintenance of vascular tone. The precise identity of the receptors which mediate these effects are unclear. The focus of Dr. Breyer?s research is the characterization of the molecular mechanism of action of PGE2 and determination of the structure-function
relationships of the PGE2 receptors. Dr. Breyer?s group is currently investigating alterations in immune/inflammatory cells function in both allergic-asthma models as well as tumor models in the PGE2 EP2 receptor knockout. They are also investigating the physiology underlying multiple abnormalities observed in these animals, with the aim of determining the role of this receptor in other disease states
including Alzheimer?s disease and infertility.

A second project in the laboratory involves using the EP3 receptors as a model system to study multiple signal transduction pathways activated by these G-protein coupled receptors. The prostaglandin EP3 receptor signals primarily through the inhibitory G-protein Gi, thereby decreasing intracellular cAMP levels, however preliminary studies have described a non-Gi coupled signal transduction pathway activated by the this receptor. Partial blockade of this novel signal transduction pathway with kinase inhibitors demonstrates that this pathway is transduced in part by a Ca++ dependent kinase pathway. Studies are underway to determine the downstream regulators which mediate this signal transduction pathway.

In addition Dr. Breyer?s lab has recently developed the technology for purifying milligram quantities of the recombinant G-protein coupled receptors. The goal of this project is to utilize this purified receptor protein to undertake biochemical characterization of the receptor protein, identify interacting proteins, and ultimately to determine the three dimensional structure of one of these receptors

Ceddia, RP, Lee, D, Maulis, MF, Carboneau, BA, Threadgill, DW, Poffenberger, G, Milne, G, Boyd, KL, Powers, AC, McGuinness, OP, Gannon, M, Breyer, RM. The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. Endocrinology, en20151693, 2015

Downey, JD, Saleh, SA, Bridges, TM, Morrison, RD, Daniels, JS, Lindsley, CW, Breyer, RM. Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere. Bioorg Med Chem Lett, 23(1), 37-41, 2013

Natarajan, C, Hata, AN, Hamm, HE, Zent, R, Breyer, RM. Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Mol Pharmacol, 83(1), 206-16, 2013

Bartlett, CS, Boyd, KL, Harris, RC, Zent, R, Breyer, RM. EP1 disruption attenuates end-organ damage in a mouse model of hypertension. Hypertension, 60(5), 1184-91, 2012

Zhou, W, Dowell, DR, Huckabee, MM, Newcomb, DC, Boswell, MG, Goleniewska, K, Lotz, MT, Toki, S, Yin, H, Yao, S, Natarajan, C, Wu, P, Sriram, S, Breyer, RM, Fitzgerald, GA, Peebles, RS. Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis. PLoS One, 7(5), e33518, 2012

Downey, JD, Sanders, CR, Breyer, RM. Evidence for the presence of a critical disulfide bond in the mouse EP3I? receptor. Prostaglandins Other Lipid Mediat, 94(1-2), 53-8, 2011 PMCID:3065360

Jewell, ML, Breyer, RM, Currie, KP. Regulation of calcium channels and exocytosis in mouse adrenal chromaffin cells by prostaglandin EP3 receptors. Mol Pharmacol, 79(6), 987-96, 2011

Swan, CE, Breyer, RM. Prostaglandin E2 modulation of blood pressure homeostasis: studies in rodent models. Prostaglandins Other Lipid Mediat, 96(1-4), 10-3, 2011

Howell, SC, Mittal, R, Huang, L, Travis, B, Breyer, RM, Sanders, CR. CHOBIMALT: a cholesterol-based detergent. Biochemistry, 49(44), 9572-83, 2010 PMCID:3030671

Smith, JP, Haddad, EV, Downey, JD, Breyer, RM, Boutaud, O. PGE2 decreases reactivity of human platelets by activating EP2 and EP4. Thromb Res, 126(1), e23-9, 2010 PMCID:2902561

Babaev, VR, Chew, JD, Ding, L, Davis, S, Breyer, MD, Breyer, RM, Oates, JA, Fazio, S, Linton, MF. Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis. Cell Metab, 8(6), 492-501, 2008 PMCID:2614698

Chen, J, Zhao, M, He, W, Milne, GL, Howard, JR, Morrow, J, Hebert, RL, Breyer, RM, Chen, J, Hao, CM. Increased Dietary NaCl induces Renal Medullary PGE2 Production and Natriuresis via the EP2 Receptor. Am J Physiol Renal Physiol, 2008 PMCID:2653111

Macias-Perez, IM, Zent, R, Carmosino, M, Breyer, MD, Breyer, RM, Pozzi, A. Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo. J Biol Chem, 283(18), 12538-45, 2008 PMCID:2335350

Guan, Y, Zhang, Y, Wu, J, Qi, Z, Yang, G, Dou, D, Gao, Y, Chen, L, Zhang, X, Davis, LS, Wei, M, Fan, X, Carmosino, M, Hao, C, Imig, JD, Breyer, RM, Breyer, MD. Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J Clin Invest, 117(9), 2496-505, 2007 PMCID:1940235

Zhou, W, Blackwell, TS, Goleniewska, K, O''neal, JF, Fitzgerald, GA, Lucitt, M, Breyer, RM, Peebles, RS. Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells. J Leukoc Biol, 81(3), 809-17, 2007

Kamiyama, M, Pozzi, A, Yang, L, DeBusk, LM, Breyer, RM, Lin, PC. EP2, a receptor for PGE2, regulates tumor angiogenesis through direct effects on endothelial cell motility and survival. Oncogene, 25(53), 7019-28, 2006

Hata, AN, Lybrand, TP, Breyer, RM. Identification of determinants of ligand binding affinity and selectivity in the prostaglandin D2 receptor CRTH2. J Biol Chem, 280(37), 32442-51, 2005

Hata, AN, Lybrand, TP, Marnett, LJ, Breyer, RM. Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol, 67(3), 640-7, 2005

Tian, C, Breyer, RM, Kim, HJ, Karra, MD, Friedman, DB, Karpay, A, Sanders, CR. Solution NMR spectroscopy of the human vasopressin V2 receptor, a G protein-coupled receptor. J Am Chem Soc, 127(22), 8010-1, 2005

Hata, AN, Breyer, RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther, 103(2), 147-66, 2004

Pozzi, A, Yan, X, Macias-Perez, I, Wei, S, Hata, AN, Breyer, RM, Morrow, JD, Capdevila, JH. Colon carcinoma cell growth is associated with prostaglandin E2/EP4 receptor-evoked ERK activation. J Biol Chem, 279(28), 29797-804, 2004

Schneider, A, Guan, Y, Zhang, Y, Magnuson, MA, Pettepher, C, Loftin, CD, Langenbach, R, Breyer, RM, Breyer, MD. Generation of a conditional allele of the mouse prostaglandin EP4 receptor. Genesis, 40(1), 7-14, 2004

Schneider, A, Zhang, Y, Zhang, M, Lu, WJ, Rao, R, Fan, X, Redha, R, Davis, L, Breyer, RM, Harris, R, Guan, Y, Breyer, MD. Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney. Kidney Int, 65(4), 1205-13, 2004

Breyer, MD, H??bert, RL, Breyer, RM. Prostanoid receptors and the urogenital tract. Curr Opin Investig Drugs, 4(11), 1343-53, 2003

Hata, Aaron N, Zent, Roy, Breyer, Matthew D, Breyer, Richard M, . Expression and molecular pharmacology of the mouse CRTH2 receptor.. J Pharmacol Exp Ther, 306, 463-70, 2003

Ochsner, Scott A, Russell, Darryl L, Day, Anthony J, Breyer, Richard M, Richards, Joanne S, . Decreased expression of tumor necrosis factor-alpha-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice.. Endocrinology, 144, 1008-19, 2003

Saito, Osamu, Guan, Youfei, Qi, Zhonghua, Davis, Linda S, K??mhoff, Martin, Sugimoto, Yukihiko, Narumiya, Shuh, Breyer, Richard M, Breyer, Matthew D, . Expression of the prostaglandin F receptor (FP) gene along the mouse genitourinary tract.. Am J Physiol Renal Physiol, 284, F1164-70, 2003

Yang, Li, Yamagata, Noboru, Yadav, Rajwardhan, Brandon, Suzanne, Courtney, Regina L, Morrow, Jason D, Shyr, Yu, Boothby, Mark, Joyce, Sebastian, Carbone, David P, Breyer, Richard M, . Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor.. J Clin Invest, 111, 727-35, 2003 PMCID:151895

Zhang, Y, Schneider, A, Rao, R, Lu, WJ, Fan, X, Davis, L, Breyer, RM, Breyer, MD, Guan, Y. Genomic structure and genitourinary expression of mouse cytosolic prostaglandin E(2) synthase gene. Biochim Biophys Acta, 1634(1-2), 15-23, 2003

Breyer, Richard M, Kennedy, Christopher R J, Zhang, Yahua, Guan, Youfei, Breyer, Matthew D, . Targeted gene disruption of the prostaglandin E2 EP2 receptor.. Adv Exp Med Biol, 507, 321-6, 2002

Cheng, H.F., Wang, S.-W., Zhang, M.-Z., McKanna, J.A., Breyer, R.M., and Harris, R.C. Prostaglandins that increase rennin production in response to ACE are not mediated by EP2 or COX-1. Am. J. Physiol., 283, R638-R646, 2002

Guan, Y, Stillman, BA, Zhang, Y, Schneider, A, Saito, O, Davis, LS, Redha, R, Breyer, RM, Breyer, MD. Cloning and expression of the rabbit prostaglandin EP2 receptor. BMC Pharmacol, 2, 14, 2002 PMCID:117438

Guan, Y., Stillman, B.A., Zhang, Y., Schneider, A., Saito, O., Davis, L.S., Redha, R., Breyer, R.M., and Breyer, M.D. Cloning and expression of the rabbit prostaglandin EP2 receptor. BMC Pharmacol., 2, 14, 2002

Imig, J.D, Breyer, M.D., and Breyer, R.M. Contribution of Prostaglandin EP2 Receptors to Renal Microvascular Reactivity in Mice. Am. J. Physiol., 283, F415-F422, 2002

Li, X., Pilbeam C.C., Pan, L., Breyer, R.M. , and Raisz, L.G. Effects of prostaglandin E2 on gene expression in primary osteoblastic cells from prostaglandin receptor knockout mice. Bone, 30, 567-573, 2002

Li, X., Tomita, M., Pilbeam, C.C., Breyer, R.M., and Raisz, L.G. Prostaglandin receptor EP2 mediates PGE2 stimulated hypercalcemia in mice in vivo. Prostaglandins Other Lipid Mediat., 67, 173-180, 2002

Montine, T.J., Milatovic, D., Morrow, J.D., and Breyer, R.M. Lipopolysaccharide- but not kainite-induced cerebral oxidative damage is EP2 receptor dependent. J. Neurochem., 83, 463-470, 2002

Montine, TJ, Milatovic, D, Gupta, RC, Valyi-Nagy, T, Morrow, JD, Breyer, RM. Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem, 83(2), 463-70, 2002

Ochsner, S.A. Russell, D.L., Day, A.J., Breyer, R.M., and Richards, J.S. Decreased expression of TNF-a stimulated gene 6 mRNA and protein in cumulus cells of the cyclooxygenase-2 knockout mouse. Endocrinology, (In Press), 2002

Qi, Z., Hao, C.M., Langenbach, R.L., Breyer, R. M., Redha, R.D., Morrow, J.D., and Breyer, M.D. Opposite effects of cyclooxygenases-1 and -2 activity on the pressor response to angiotensin II. J.Clin.Invest., 110, 61-69, 2002

Qi, Z, Hao, CM, Langenbach, RI, Breyer, RM, Redha, R, Morrow, JD, Breyer, MD. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest, 110(1), 61-9, 2002 PMCID:151026

Breyer, MD, Breyer, RM. G protein-coupled prostanoid receptors and the kidney. Annu Rev Physiol, 63, 579-605, 2001

Breyer, RM. Prostaglandin EP(1) receptor subtype selectivity takes shape. Mol Pharmacol, 59(6), 1357-9, 2001

Breyer, RM, Bagdassarian, CK, Myers, SA, Breyer, MD. Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol, 41, 661-90, 2001

Figueroa, D.J., Breyer, R.M., DeFoe, S.K., Kargman, S., Daugherty, B.L., Waldburger, K., Zhizen, Z., Jones, T.R., Austin, C.P., and Evans, J.P. Expression of the cysteinyl leukotriene 1 (CysLT1) receptor in normal human lung and peripheral blood leukocytes. Am. J. Resp. Crit Care Med., 163, 226-233, 2001

Figueroa, DJ, Breyer, RM, Defoe, SK, Kargman, S, Daugherty, BL, Waldburger, K, Liu, Q, Clements, M, Zeng, Z, O'Neill, GP, Jones, TR, Lynch, KR, Austin, CP, Evans, JF. Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med, 163(1), 226-33, 2001

Fortner, C.N., Breyer, R.M., and Paul, R.J. EP2 Receptors Mediate Airway Relaxation To Substance P, ATP, And Prostaglandin E2. Am. J. Physiol., 281, L469-L474, 2001

Guan, Y, Zhang, Y, Schneider, A, Davis, L, Breyer, RM, Breyer, MD. Peroxisome proliferator-activated receptor-gamma activity is associated with renal microvasculature. Am J Physiol Renal Physiol, 281(6), F1036-46, 2001

Guan, Y, Zhang, Y, Schneider, A, Riendeau, D, Mancini, JA, Davis, L, K??mhoff, M, Breyer, RM, Breyer, MD. Urogenital distribution of a mouse membrane-associated prostaglandin E(2) synthase. Am J Physiol Renal Physiol, 281(6), F1173-7, 2001

Guan, Y., Zhang, Y., Schneider, A., Davis, L., Breyer, R.M., and Breyer, M.D. Perixosome proliferator-activated receptor γ(PPARγ) activity is associated with renal microvasculature. Am. J. Physiol., 28, F1036-F1046, 2001

Guan, Y., Zhang, Y., Schneider, A., Riendeau, D., Mancini, J.A., Davis, L., Komhoff, M., Breyer, R.M., and Breyer, M.D. Urogenital distribution of a mouse membrane-associated prostaglandin E2 synthase. Am. J. Physiol., 281, F1173-F1177, 2001

Matsumoto, H., Ma, W. Smalley, W., Trzaskos, J., Breyer, R.M., and Dey, S.K. Diversification of cyclooxygenase -2 derived prostaglandins in ovulation and implantation. Biol. Reprod., 64, 1557-1565, 2001

Stecenko, A.A., King, G., Torii, K., Breyer, R.M., Dworski, R., Blackwell, T.S., Christman, J.W., and Brigham, K.L. Dysregulated cytokine production by cultured human cystic fibrosis bronchial epithelial cells. Inflammation, 25, 145-155, 2001

Stecenko, AA, King, G, Torii, K, Breyer, RM, Dworski, R, Blackwell, TS, Christman, JW, Brigham, KL. Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells. Inflammation, 25(3), 145-55, 2001

Breyer, MD, Breyer, RM. Prostaglandin receptors: their role in regulating renal function. Curr Opin Nephrol Hypertens, 9(1), 23-9, 2000

Breyer, MD, Breyer, RM. Prostaglandin E receptors and the kidney. Am J Physiol Renal Physiol, 279(1), F12-23, 2000

Breyer, RM, Kennedy, CR, Zhang, Y, Breyer, MD. Structure-function analyses of eicosanoid receptors. Physiologic and therapeutic implications. Ann N Y Acad Sci, 905, 221-31, 2000

Li, X., Okada, Y., Pilbeam C.C., Kennedy, C.R.J., Breyer, R.M. , and Raisz, L.G. Knockout of the Prostaglandin EP2 Receptor Impairs Osteoclastogenesis in vitro . Endocrinology, 141, 2054-2061, 2000

Sheller, J. R., Mitchell, D., Meyrick, B., Oates, J. A. and Breyer, R. M. The EP2 Receptor Mediates Bronchodilation in Mice. J. Applied Physiol, 88, 2214-2218, 2000

Zhang, Y, Guan, Y, Schneider, A, Brandon, S, Breyer, RM, Breyer, MD. Characterization of murine vasopressor and vasodepressor prostaglandin E(2) receptors. Hypertension, 35(5), 1129-34, 2000

Zhang, Y., Guan Y., Schneider, A., Brandon, S., Breyer, R. M., and Breyer M. D. Characterization of murine vasopressor and vasodepressor prostaglandin E2 receptors. Hypertension, 35, 1129-1134, 2000

Audoly, L., Ma, L., Feoktistov, I. Breyer, M.D. and Breyer, R. M. EP3 receptor activation of cAMP response element mediated gene transcription. J. Pharmacol. Exper. , 289, 140-148, 1999

Audoly, LP, Ma, L, Feoktistov, I, de Foe, SK, Breyer, MD, Breyer, RM. Prostaglandin E-prostanoid-3 receptor activation of cyclic AMP response element-mediated gene transcription. J Pharmacol Exp Ther, 289(1), 140-8, 1999

Guan, YF, Zhang, YH, Breyer, RM, Davis, L, Breyer, MD. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia, 1(4), 330-9, 1999 PMCID:1508103

Kennedy, C. R. J., Zhang, Y., Brandon, S, Guan, Y., Coffee K., Funk, C. D., Magnuson, M. A., Oates, J. A., Breyer, M. D., and Breyer, R. M. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor . Nature Medicine, 5, 217-220, 1999

Kennedy, CR, Zhang, Y, Brandon, S, Guan, Y, Coffee, K, Funk, CD, Magnuson, MA, Oates, JA, Breyer, MD, Breyer, RM. Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nat Med, 5(2), 217-20, 1999

Stillman, BA, Breyer, MD, Breyer, RM. Importance of the extracellular domain for prostaglandin EP(2) receptor function. Mol Pharmacol, 56(3), 545-51, 1999

Breyer, MD, Zhang, Y, Guan, YF, Hao, CM, Hebert, RL, Breyer, RM. Regulation of renal function by prostaglandin E receptors. Kidney Int Suppl, 67, S88-94, 1998

Guan, Y, Zhang, Y, Breyer, RM, Fowler, B, Davis, L, H??bert, RL, Breyer, MD. Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor. J Clin Invest, 102(1), 194-201, 1998 PMCID:509081

Stillman, BA, Audoly, L, Breyer, RM. A conserved threonine in the second extracellular loop of the human EP2 and EP4 receptors is required for ligand binding. Eur J Pharmacol, 357(1), 73-82, 1998

Audoly, L, Breyer, RM. Substitution of charged amino acid residues in transmembrane regions 6 and 7 affect ligand binding and signal transduction of the prostaglandin EP3 receptor. Mol Pharmacol, 51(1), 61-8, 1997

Audoly, L, Breyer, RM. The second extracellular loop of the prostaglandin EP3 receptor is an essential determinant of ligand selectivity. J Biol Chem, 272(21), 13475-8, 1997

Audoly, L.P., and Breyer, R.M. The second extracellular loop of the prostaglandin EP3 receptor is an essential determinant of ligand selectivity . J. Biol. Chem., 272, 13475-13478, 1997

Feoktistov, I, Breyer, RM, Biaggioni, I. Prostanoid receptor with a novel pharmacological profile in human erythroleukemia cells. Biochem Pharmacol, 54(8), 917-26, 1997

Breyer, M. D., Jacobson, H. R., Davis, L.S., and Breyer, R. M. Differential Localization of Prostaglandin E Receptor Subtypes in Human Kidney. Am. J. Physiol, 270, F912-F918, 1996

Breyer, R. M., Emeson, R. B., Breyer, M. D., Davis, L.S., Abromson, R.M., and Ferrenbach, S. F. Alternative Splicing Generates Multiple Isoforms of a Rabbit Prostaglandin E2 Receptor. J. Biol. Chem., 6163, 6169, 1994

Breyer, RM, Emeson, RB, Tarng, JL, Breyer, MD, Davis, LS, Abromson, RM, Ferrenbach, SM. Alternative splicing generates multiple isoforms of a rabbit prostaglandin E2 receptor. J Biol Chem, 269(8), 6163-9, 1994

Breyer, MD, Jacobson, HR, Davis, LS, Breyer, RM. In situ hybridization and localization of mRNA for the rabbit prostaglandin EP3 receptor. Kidney Int, 44(6), 1372-8, 1993

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