Department of Cell Biology and Physiology

Faculty

Eric R. Prossnitz, Ph.D.

Research Interests

G protein-coupled receptors represent the largest family of signal transducing molecules. In all, there are approximately 600-1000 G protein-coupled receptor genes present in the human genome. Because they are involved in almost every aspect of human physiology, G protein-coupled receptors are the targets of nearly one half of prescription drugs on the market today. One area of interest focuses on understanding the mechanisms of activation and inactivation of this receptor family.

As a model system, we utilize the N-formyl peptide chemoattractant receptor (FPR) found predominantly on leukocytes. This receptor mediates chemotactic and inflammatory responses within the immune system. Our major areas of interest focus on mechanisms of receptor processing following activation and the role of arrestins in these processes. We have demonstrated that although the phosphorylated FPR binds arrestin, this interaction is not involved in the internalization of the receptor, contrary to what is observed with many other G protein-coupled receptors. However, arrestin is required for receptor recycling back to the cell surface. In addition, activation of the FPR and numerous other GPCRs induces apoptosis in cells devoid of arrestins. We are currently investigating the mechanisms involved in these processes.

Another focus of the lab is the novel G protein-coupled estrogen receptor GPR30. This is a classic 7-transmembrane GPCR that we have shown, unlike other GPCRs, resides in the endoplasmic reticulum (Science 2005, 307: 1625-1630). From this location, it binds estrogen and activates numerous cellular signaling pathways including calcium mobilization and PI3K activation. Although classical estrogen receptors (ERa) can activate many of the same cellular effectors as GPR30, the signaling pathways differ for the two receptors. In order to quantitate and localize estrogen binding, we have developed a novel fluorescent estrogen analog that localizes with both classical estrogen receptors and GPR30. Recent screening efforts have led to the identification of the first GPR30-selective agonist, G-1 (Nature Chem Biol 2006 2: 207-12). Current work is addressing the role of this newest estrogen receptor in cellular function, normal physiology and disease.

Education, Honors and Professional Experience

1985, B.Sc., Biochemistry, University of Victoria (Canada)
1989, Ph.D., Biochemistry, University of California, Berkeley, CA
1985-1989 The 1967 Science and Engineering Scholarship, NSERC , Canada
1989-1993, Research Associate, The Scripps Research Institute, La Jolla, CA
1991-1993 Human Frontiers of Science Program Organization Long Term Fellowship
1993-1994, Senior Research Associate, The Scripps Research Institute, La Jolla, CA
1994-1997, Assistant Professor, The Scripps Research Institute, La Jolla, CA
1997-2000 Assistant Professor, The University of New Mexico
2000-2005 Associate Professor, The University of New Mexico
2005-present Professor, The University of New Mexico

Current Lab Personnel

Post-Doctoral fellows
Hugh Mitchell, Ph.D.

Graduate students
Sean Biggs
Jennifer Carter (Chemistry Dept.)
Megan Dennis
Angela Field
Tapan Nayak
Whitney Petrie

MD/Ph.D. student
Brant Wagener

Research staff
Daniel Cimino

Selected Publications

Bologa, C.G., Revankar, C.M., Young, S.M., Edwards, B.S., Arterburn, J.B., Kiselyov, A.S., Parker, M.A., Tkachenko, S.E., Savchuck, N.P., Sklar, L.A., Oprea, T.I., Prossnitz, E.R. (2006) Virtual and Biomolecular Screening Converge on a Selective Agonist for GPR30.
Nat Chem Biol 2, 207-12.

Potter, R.M., Maestas, D.C., Cimino, D.F., Prossnitz, E.R. (2006) Regulation of N-Formyl Peptide Receptor Signaling and Trafficking by Individual Carboxyl-Terminal Serine and Threonine Residues.
J Immunol 176, 5418-25.

Revankar, C.M., Cimino, D.F., Sklar, L.A., Arterburn, J.B., Prossnitz, E.R. (2005) A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling.

 Science 307, 1625-1630.

Key, T.A., Vines, C.M., Wagener, B.M., Gurevich, V.V., Sklar, L.A., Prossnitz, E.R. (2005) Inhibition of chemoattractant N-formyl Peptide receptor trafficking by active arrestins.
Traffic 6, 87-99

Prossnitz, E.R. (2004) Novel roles for arrestins in the post-endocytic trafficking of G protein-coupled receptors.
Life Sciences 75, 893-899.

Vines, C.M., Prossnitz, E.R. (2004) Mechanisms of G protein-coupled receptor-mediated degranulation.
FEMS Microbial Lett 236, 1-6.

Revankar, C.M., Vines, C.M., Cimino, D.F., Prossnitz, E.R. (2004) Arrestins Block G Protein-coupled Receptor-mediated Apoptosis.
J Biol Chem 279, 24578-84.

Vines, C.M., Revankar, C.M., Maestas, D.C., LaRusch, L.L., Cimino, D.F., Kohout, T.A., Lefkowitz, R.J., Prossnitz, E.R.(2003) N-formyl peptide receptors internalize but do not recycle in the absence of arrestins.
J. Biol. Chem. 278, 41581-41584 .

Shi, M., Bennett, T.A., Cimino, D.F., Maestas, D.C., Foutz, T.D., Gurevich, V.V., Sklar, L.A., Prossnitz, E.R.(2003) Functional capabilities of an N-formyl peptide receptor-Gai2 fusion protein: Assemblies with G proteins and arrestins.
Biochemistry 42, 7283-7293.

Key, T. A., Foutz, T. D., Gurevich, V. V., Sklar, L. A. & Prossnitz, E. R. (2003) N-formyl peptide receptor phosphorylation domains differentially
regulate arrestin and agonist affinity.
J. Biol. Chem. 278, 4041-4047.

Vines, C.M., Xue, M., Cimino, D., Maestas, D.C., Prossnitz, E.R. (2002) Regulation of N-formyl peptide-mediated degranulation by receptor phosphorylation.
 J. Immunol. 169, 6760-6766.

Sklar, L.A., Edwards, B.S., Graves, S.W., Nolan, J.P., Prossnitz, E.R. (2002) Flow cytometric analysis of ligand-receptor interactions and molecular assemblies.
Annu Rev Biophys Biomol Struct 31, 97-119.

Potter, R.M., Key, T.A., Gurevich, V.V., Sklar, L.A., Prossnitz, E.R. (2002) Arrestin variants display differential binding characteristics for the phosphorylated N-formyl peptide receptor carboxy terminus.
J. Biol. Chem. 277, 8970-8.

Graham, T.E., Prossnitz, E.R., Dorin, R.I. (2002) Dexras/AGS-1 inhibits signal transduction form the Gi-coupled formyl peptide receptor to Erk-1/2 MAP kinases.
J Biol Chem 277, 10876-8.

Key, T.A., Bennett, T.A., Gurevich, V.V., Sklar, L.A., Prossnitz, E.R. (2001) Regulation of solubilied N-formyl peptide receptor agonist affinity by reconstitution with b-arrestins and heterotrimeric G proteins.
 J. Biol. Chem. 276, 49204-12.

Bennett, T.A., Gurevich, V.V., Sklar, L.A., Prossnitz, E.R. (2001) Partial phosphorylation of the N-formyl peptide receptor inhibits G protein association independent of arrestin binding.
 J. Biol. Chem. 276, 49195-203.

Chigaev, A., Blenc, A.M., Braaten, J.V., Kumaraswamy, N., Kepley, C.L., Andrews, R.P., Oliver, J.M., Edwards, B.S., Prossnitz, E.R., Larson, R.S., Sklar, L.A. (2001) Real-time analysis of the affinity regulation of alpha4-integrin: the physiologically activated receptor is intermediate in affinity between resting and Mn2+ or antibody activation.
J Biol Chem 276 48670-8.

Bennett, T.A., Key, T.A., Gurevich, V.V., Neubig, R., Prossnitz, E.R., Sklar, L.A. (2001) Real-time analysis of G Protein-coupled receptor reconstitution in a solubilized system. J. Biol. Chem. 276, 22453-22460.
J. Biol. Chem. 276, 22453-22460.

Gilbert, T.L., Bennett, T.A., Maestas, D.C., Cimino, D.F., Prossnitz, E.R. (2001) Internalization of the human N-formyl peptide and C5a chemoattractant receptors occurs via clathrin-independent mechanisms.
Biochemistry 40, 3467-3475.

Edwards, B.S., Kuckuck, F.W., Prossnitz, E.R., Ransom, J.T., Okun, A., Sklar, L.A. (2001) Plug flow cytometry extends analytical capabilities in cell adhesion and receptor pharmacology.
Cytometry 43, 211-216.

Edwards, B.S., Kuckuck, F.W., Prossnitz, E.R., Ransom, J.T., Sklar, L.A. (2001) HTPS Flow Cytometry: A novel platform for automated high throuput drug discovery and characterization. J. Biomol. Screening 6, 83-90.

Sklar, L.A., Vilven, J., Lynam, E., Neldon, D., Bennett, T.A., Prossnitz, E.R. (2000) Solubilization and display of seven transmembrane receptors on beads for real time fluorescence and flow cytometric analysis. Biotechniques 28, 976-985.

Rane, M.J., Prossnitz, E.R., Arthur, J.M., Ward, R.A., McLeish, K.R. (2000) Deficient homologous desensitization of formyl peptide receptors stably expressed in undifferentiated HL-60 cells.
Biochem Pharmacol 60, 179-187.

Bennett, T.A., Maestas, D.C., Prossnitz, E.R. (2000) Arrestin binding to the G protein-coupled N-formyl peptide receptor is regulated by the conserved 'DRY' sequence.
 J Biol Chem. 275, 24590-24594

Prossnitz, E.R., Gilbert, T.L., Chiang, S., Campbell, J.J., Qin, S., Newman, W., Sklar, L.A., Ye, R.D. (1999) Multiple activation steps of the N-formyl peptide receptor.
 Biochemistry 38, 2240-2247.

Maestas, D.C., Potter, R., Prossnitz, E.R. (1999) Differential phosphorylation paradigms direct desensitization and internalization of the N-formyl peptide receptor.
J. Biol. Chem.  274, 29791-29795.

Hsu, M.H., Chiang, S.C., Ye, R.D., Prossnitz, E.R. (1997) Phosphorylation of the N-formyl peptide receptor is required for receptor internalization but not chemotaxis.
J Biol Chem 272, 29426-9.

Prossnitz, E.R., Ye, R.D. (1997) The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function. Pharmacol Ther 74, 73-102.

Prossnitz, E.R. (1997) Desensitization of N-formylpeptide receptor-mediated activation is dependent upon receptor phosphorylation.
J Biol Chem 272, 15213-9.

Kew, R.R., Peng, T., DiMartino, S.J., Madhavan, D., Weinman, S.J., Cheng, D., Prossnitz, E.R. (1997) Undifferentiated U937 cells transfected with chemoattractant receptors: a model system to investigate chemotactic mechanisms and receptor structure/function relationships. J Leukoc Biol 61, 329-37.