Uniformed Services University of the Health Sciences
Department of Pharmacology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3232
FAX: (301) 295-3220
G-protein coupled receptors (GPCRs) represent the primary mechanism by which cells sense alterations in their external environment and convey that information to the cells' interior. Abnormalities of delicate signaling mediated by this mechanism are often attributed to diseases and disorders, e.g. hypertension, preeclampsia, hypertrophy, cancer, fibrosis, obesity, diabetes, and human CNS diseases. Thus, study of mechanistic and functional properties of these GPCRs will help understand the pathogenesis of many diseases.
Intervention at the level of GPCRs has a proven history of being excellent therapeutic targets. More than 50% of drugs on market target this superfamily of receptors with known native ligands. The current total market for GPCR drugs such as antihistamines, AT1 antagonists, and beta-blockers is $60 billion. Out of 800 human GPCRs identified by human genome projects, more than 600 remain orphan receptors for which the native ligands are unknown. With current techniques available, identifying the native ligand (deorphanization) requires about 5 years and costs millions of dollars per receptor. This has become an apparent bottleneck for drug discovery that targets GPCRs. It also hampers biomedical advance on many fronts. Thus, study of mechanistic and functional properties of these GPCRs will expedite drug discovery and open up new avenues for biomedical research. This represents a major challenge in functional genomics.
Differences in structure-function and signal transduction of subtype receptors represent another major challenge to understand the role of GPCRs in nature and biomedicine. Elucidation of these differences and their mechanisms will greatly advance receptor biology, pharmacology and therapeutics.
G protein-coupled Angiotensin II receptors are widely expressed and associated with hypertension, cardiac hypertrophy, renal fibrosis, diabetes, and stress. These receptors are the model system that is studied in our laboratory for understanding ligand recognition, angiotensin II-dependent and -independent activation, inverse agonism, internalization, G protein coupling, EGF receptor transactivation, and AT2-mediated inhibitory signaling.
The other major areas of current research include deorphanization, receptor dimerization, endoplasmic reticulum (ER) membrane insertion and topology, and receptor splicing variants. The forth research area focuses on neurotrophin signaling. Brain and spinal cord injury is a devastating condition often affecting young and health individuals, especially, the military personnel. The most important therapy is to promote the repair and recovery of injured nerve cells. However, the poor understanding of the systemic signaling that regulates neuronal growth, apoptosis, repair and recovery has hampered advances in the treatment. The NGF (nerve growth factor) family of neurotrophins including BDNF, NT-3 and NT-4/5, play pivotal roles in the development, maintenance, and recovery/repair of central and peripheral nervous systems. There are two distinct classes of neurotrophin receptors, specific Trk tyrosine kinase receptors and the shared p75 neurotrophin receptor (p75NTR). The Trk receptors bind specific neurotrophins whereas the p75NTR promiscuously binds all neurotrophins. Moreover, the p75NTR also binds all three myelin proteins of MAG, NogoA, and OMgp. Remarkably, accumulating evidence indicates that binding of the neurotrophins and the myelin proteins to p75NTR activates inhibitory signaling, leading to growth inhibition and apoptosis. The p75NTR-mediated inhibitory signals might compromise the ability of neurotrophins in stimulating neurite outgrowth and intraspinal sprouting. In addition, p75NTR also associates with the Trk receptors in the presence of neurotrophins, complicating the signaling network. Therefore, systemic analysis of the neurotrotrophin signaling through binding to the receptors might open novel research and therapeutic avenues.
Recently, this laboratory has developed interests in developing antibody-based therapeutics using protein engineering and targeted evolution. Another ongoing project is to understand how expression of reprogramming transcription factors such as Oct3 and Nanog is regulated. In addition, we collaborate with Dr. Gorodeski at Case Western Reserve University on P2X7 related project. We also collaborate with Dr. Wang at Wuhan University School of Medicine on hepatic fibrosis and understanding the mechanism of epigenetic modification of GR in the development of IUGR and metabolic syndrome induced by fetal exposure of environmental substances. Bimolecular fluorescence complementation (BiFC) and ligand-assisted TR-FRET (time resolved fluorescence resonance energy transfer) are modified and developed in the laboratory to detect receptor dimerization, and protein-protein interaction.
Feng YH, Sun Y, and Douglas JG. G??-Independent Constitutive Association of Gs? with SHP-1 and Angiotensin II Receptor AT2 Is Essential in AT2-mediated Activation of SHP-1. Proc. Natl. Acad. Sci. USA 99:12049-12054 (2002)
Wang Q, Li X, Wang L, Feng YH, Zeng R, Gorodeski GI. Anti-apoptotic effects of estrogen in normal and in cancer human cervical epithelial cells. Endocrinology 145:5568-79 (2004)
Wang Q, Wang L, Feng YH, Li X, Zeng R, Gorodeski GI. P2X7-receptor-mediated apoptosis of human cervical epithelial cells. Am J Physiol Cell Physiol. 287:C1349-58 (2004)
Wang L, Feng YH, Gorodeski GI. EGF facilitates epinephrine inhibition of P2X7-receptor pore formation by modulating 2-adrenoceptor internalization and recycling: a signaling network. Endocrinology 146:164-74 (2005)
Feng YH, Zhou LY, Sun Y, and Douglas JG. Functional Diversity of AT2 Receptor Orthologues in Closely related Eutherian. Kidney Intl 67:1731-8 (2005)
Feng YH, Wang L, Wang Q, Li X, Zeng R, Gorodeski GI. ATP ligation stimulates GRK-3 - mediated phosphorylation and -arrestin-2- and dynamin-dependent internalization of the P2X7-receptor. Am J Physiol Cell Physiol. 288:C1342-56 (2005)
Feng YH, Zhou L, Qiu R, and Robin Zeng. Single mutations at Asn295 and Leu305 in the cytoplasmic half of TM7 of the AT1 receptor induce promiscuous agonist specificity for angiotensin II fragments - A PSEUDO-CONSTITUTIVE ACTIVITY. Mol Pharmacol 68:347-55 (2005)
Feng YH, Ding Y, Ren S, Xu C, Karnik SS. Unconventional homologous internalization of the AT1 receptor induced by G protein-independent signals. Hypertension 46:419-25 (2005)
Yan YE, Wang H, Feng YH. Alterations of placental cytochrome P450 1A1 and P-glycoprotein in tobacco-induced intrauterine growth retardation in rats. Acta Pharmacol Sin 26:1387-94 (2005)
Feng YH, Li X, Wang L, Zhou L, Gorodeski GI. A truncated P2X7 receptor variant (P2X7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem. 281:17228-37 (2006)
Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously Expressed Truncated P2X7 Receptor Lacking the C-Terminus is Preferentially Upregulated in Epithelial Cancer Cells and Fails to Mediate Ligand-Induced Pore Formation and Apoptosis. Nucleosides Nucleotides Nucleic Acids. 25:1271-6 (2006)
Li X, Zhou L, Feng YH, Abdul-Karim FW, Gorodeski GI. The P2X7 Receptor: A Novel Biomarker of Uterine Epithelial Cancers. Cancer Epidemiol Biomarkers Prev. 15:1906-13 (2006)
Feng YH, Li X, Zeng R, Gorodeski GI. Endogenously expressed truncated P2X7 receptor lacking the C-terminus is preferentially upregulated in epithelial cancer cells and fails to mediate ligand-induced pore formation and apoptosis. Nucleosides Nucleotides Nucleic Acids. 25(9-11):1271-6 (2006)
Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H. Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 59: 245-51 (2007)