BIOGRAPHICAL SKETCH

Provide the following information for the key personnel in the order listed on Form Page 2.

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NAME

Lonny R. Levin

POSITION TITLE

Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

YEAR(s)

FIELD OF STUDY

Cornell University, Ithaca, NY

State University of New York, Stonybrook, NY

Johns Hopkins School of Medicine, Baltimore, MD

B.S.

Ph.D.

1983

1989

1994

Biology/Genetics

Genetics

Post-Doctoral research

A. Positions & Honors:

1983-89 Graduate Student, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

1989-94 Post-Doctoral Fellow, Department of Molecular Genetics and Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, MD.

1994-2001 Assistant Professor, Department of Pharmacology, Weill Medical College of Cornell University, New York, NY.

2001-2009 Associate Professor Department of Pharmacology, Weill Medical College of Cornell University, New York, NY.

2009- Professor Department of Pharmacology, Weill Medical College of Cornell University, New York, NY.

2003 Hirschl/Weill-Caulier Medical Scholar

B. Selected bibliography:

Broek, D., T. Toda, T. Michaeli, L. Levin, C. Birchmeier, M. Zoller, S. Powers, and M. Wigler (1987). The S. cerevisiae CDC25 gene product regulates the RAS/Adenylate cyclase pathway. Cell 48: 789-799.

Levin, L.R., J. Kuret, K.E. Johnson, S. Powers, S. Cameron, T. Michaeli, M. Wigler, and M.J. Zoller (1988). A mutation in the catalytic subunit of cAMP-dependent protein kinase that disrupts regulation. Science 240: 68-70.

Cameron, S., L. Levin, M. Zoller, and M. Wigler (1988). cAMP-independent control of sporulation, glycogen metabolism, and heat shock resistance in Saccharomyces cerevisiae. Cell 53: 555-566.

Zoller, M.J., J. Kuret, S. Cameron, L. Levin, and K.E. Johnson (1988). Purification and characterization of C₁, the catalytic subunit of Saccharomyces cerevisiae cAMP-dependent protein kinase encoded by TPK1. J. Biol. Chem. 263: 9142-9148.

Levin, L.R., and M.J. Zoller (1990). Association of catalytic and regulatory subunits of cAMP-dependent protein kinase requires a negatively charged side group at a conserved threonine. Mol. Cell. Biol. 10: 1066-1075.

Zoller, M.J., K.E. Johnson, W. Yonemoto, and L. Levin (1991). Functional expression of mammalian adenosine cyclic monophosphate-dependent protein kinase in Saccharomyces cerevisiae. Meth. Enzymol. 200: 605-627.

Glass, D.B., M.J. Feller, L.R. Levin, and D.A. Walsh (1992). Structural basis for the low affinities of yeast cAMP-dependent and mammalian cGMP-dependent protein kinases for protein kinase inhibitor peptides. Biochemistry 31:1728-1734.

Levin, L.R., P.-L. Han, P.M. Hwang, P.G. Feinstein, R.L. Davis, and R.R. Reed (1992). The Drosophila learning and memory gene, rutabaga, encodes a Ca²⁺/Calmodulin-responsive adenylyl cyclase. Cell 68: 479-489.

Han, P.-L., L.R. Levin, R.R. Reed, and R.L. Davis (1992). Preferential expression of the Drosophila rutabaga gene in mushroom bodies, neural centers for learning in insects. Neuron 9: 619-627.

Insall, R., A. Kuspa, P.J. Lilly, G. Shaulsky, L.R. Levin, W.F. Loomis, and P. Devreotes (1994). Restriction enzyme mediated integration cloning of CRAC, a protein required for Dictyostelium adenylyl cyclase activation. J. Cell Biol. 126:1537-1545.

Levin, L.R. and R.R. Reed (1995). Identification of functional domains of adenylyl cyclase using in vivo chimeras. J. Biol. Chem. 270:7573-7579.

Iourgenko, V., B. Kliot, M.J. Cann, and L.R. Levin (1997). Cloning and characterization of a Drosophila adenylyl cyclase homologous to mammalian type IX. FEBS Letters 413:104-108.

Cann, M.J. and L.R. Levin (1998). Genetic characterization of adenylyl cyclase function. In Advances in Second Messenger and Phosphoprotein Research: Adenylyl Cyclases, D.M.F. Cooper, ed. (New York: Raven Press), Chapter 6:121-135.

Buck*, J., M.L. Sinclair*, L. Schapal, M.J. Cann, and L.R. Levin (1999). Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc. Natl. Acad. Sci. 96:79-84.

Cann, M.J. and L.R. Levin (2000) Restricted expression of a truncated adenylyl cyclase in the cephalic furrow of Drosophila melanogaster. Dev. Genes, & Evol. 210: 34-40.

Iourgenko, V. and L.R. Levin (2000) A calcium inhibited Drosophila adenylyl cyclase. Biochemica et Biophysica Acta 1495: 125-139.

Cann, M.J., E. Chung, and L.R. Levin (2000) A new family of adenylyl cyclase genes in the male germline of Drosophila melanogaster. Dev. Genes, & Evol 210:200-206.

Sinclair, M.L., X.-Y. Wang, M. Conti, J. Buck, D.J. Wolgemuth, and L.R. Levin (2000). Selective expression of soluble adenylyl cyclase in male germ cells, Mol. Rep. Dev. 56:6-11.

Chen*, Y., M.J. Cann*, T.N. Litvin, V. Iourgenko, M.L. Sinclair, L.R. Levin, and J. Buck (2000). Adenylyl cyclase is an evolutionarily conserved bicarbonate sensor. Science 289: 625-628..

Wuttke, M.S., J. Buck, and L.R. Levin (2001). Bicarbonate-regulated soluble adenylyl cyclase. Journal of the Pancreas. 2: 154-158.

Zippin, J.H., L.R. Levin, and J. Buck (2001). Bicarbonate/CO₂ responsive soluble adenylyl cyclase as a putative metabolic sensor. Trends in Endocrinology and Metabolism. 12: 366-370.

Buck, J., M.L. Sinclair, and L.R. Levin (2002). Purification of soluble adenylyl cyclase. Methods in Enzymology (G proteins), 345: 95-105.

Cann, M.J., and L.R. Levin (2002). Improved methods for identification of novel transmembrane adenylyl cyclase isoforms. Methods in Enzymology (G proteins), 345: 150-159.

Zippin, J.H.*, Chen, Y.*, Nahirney, P.*, Kamenetsky, M., Wuttke, M.S., Fischman, D.A., Levin, L.R. and Buck, J. (2003). Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. FASEB Journal 17: 82-84.

Sun, X.C., Zhai, C.-B., Miao, C., Chen, Y., Levin, L.R., Buck, J., and Bonanno, J.A. (2003). HCO₃^-dependent soluble adenylyl cyclase activates the cystic fibrosis transmembrane conductance regulator in corneal endothelium. Am J Physiol Cell Physiol 284: C1114-1122.

Litvin, T.N., Kamenetsky, M., Zarifyan, A., Buck, J. and Levin, L.R. (2003). Kinetic Properties of 'soluble' adenylyl cyclase: synergism between calcium and bicarbonate. J. Biol. Chem. 278:15922-15926.

Pastor-Soler, N., Beaulieu, V., Litvin, T.N., Da Silva, N., Chen, Y., Brown, D., Buck, J., Levin, L.R., and Breton, S. (2003). Bicarbonate regulated adenylyl cyclase (sAC) is a sensor that regulates pH-dependent V-ATPase recycling. J. Biol. Chem.278:49523-49529.

Zippin, J.H, Farrel, J., Huron, D., Hess, K.C., Fischman, D.A., Levin, L.R. and Buck, J. (2004) Bicarbonate responsive `soluble` adenylyl cyclase defines a nuclear cAMP microdomain. J. Cell. Biol. 164:527-534.

Kobayashi, M., Buck, J., and Levin, L.R. (2004). Conservation of functional domain structure in bicarbonate-regulated 'soluble' adenylyl cyclases in bacteria and eukaryotes. Dev. Genes & Evol. 214:503-509.

Steegborn, C., Litvin, T.N., Levin, L.R., Buck, J., and Wu, H. (2005). Bicarbonate activation of adenylyl cyclase via promotion of the catalytic cycle: active site closure and metal recruitment. Nature Str. & Mol. Biol. 12:32-37.

Han, H., Stessin, A.M., Roberts, J., Hess, K.C., Gautam, N., Kamenetsky, M., Lou, O., Hyde, E., Nathan, N., Muller, W.A., Buck, J., Levin, L.R., and Nathan, C. (2005). Role of Calcium-Sensing Soluble Adenylyl Cyclase in TNF Signal Transduction in Human Neutrophils. J. Exp. Med. 202:353-361.

Steegborn, C.*, Litvin, T.N.*, Hess, K., Buck, J, Levin, L.R., and Wu, H. (2005). Molecular mechanism of adenylyl cyclases inhibition by catechol estrogen. J. Biol. Chem. 280:31754-9.

Hess, K.C.*, Jones, B.H.*, Marquez, B., Chen, Y., Ord, T.S., Kamenetsky, M., Myamoto, C., Zippin, J.H., Kopf, G.S., Suarez, S.S., Levin, L.R.*, Williams, C.J.*, Buck, J.*, and Moss, S.B.* (2005). ‘Soluble' Adenylyl Cyclase mediates Multiple Specific Signaling Events in Sperm Required for Fertilization. Dev. Cell 9:249-259.

Klengel, T.*, Liang, W-J.*, Chaloupka, J.A.*, Ruoff, C., Schroppel, K., Naglik, J.R., Eckert, S.E., Gewiss, E., Haynes, K., Tuitte, M.F., Levin, L.R., Buck, J., and Muhlschlegel, F.A. (2005). Fungal adenylyl cyclase integrates CO2 sensing with cAMP signalling and virulence. Curr. Biol.15: 2021-2026.

Mogensen, E.G., Janbon, G., Chaloupka, J., Steegborn, C., Fu, M.S., Moyrand, F., Klengel, T., Pearson, D.S., Geeves, M.A., Buck, J., Levin, L.R. and Muhlschlegel, F.A. (2006). Cryptococcus senses CO2 through the carbonic anhydrase Can2 and the adenylyl cyclase Cac1. Eukaryotic Cell5:103-111.

Chaloupka, J.A., Bullock, S.A., Iourgenko, V., Levin, L.R., and Buck, J. (2006). Auotinhibitory regulation of soluble adenylyl cyclase. Mol. Repro. & Dev.73: 361-368.

Stessin, A.M., Zippin, J.H., Kamenetsky, M., Hess, K.C., Buck, J., and Levin, L.R. (2006). Soluble adenylyl cyclase mediates NGF-induced activation of RAP1. J. Biol. Chem. 281: 17253-17258.

Kamenetsky, M., Middelhaufe, S. Bank, E.M., Levin, L.R., Buck, J., and Steegborn, C. (2006). Molecular details of cAMP generation in mammalian cells: A tale of two systems. J. Mol. Biol. 362: 623-629.

Wu, K.Y., Zippin, J.H., Huron, D.R., Kamenetsky, M., Hengst, U., Buck, J., Levin, L.R., and Jaffrey, S.R. (2006). Soluble adenylyl cyclase is required for netrin-1 signaling in nerve growth cones.Nature Neurosci. 9: 1257-1264.

Beltran, C., Vacquier, V.D., Moy, G., Chen, Y., Buck, J., Levin, L.R., and Darszon, A. (2007). Particulate and soluble adenylyl cyclases participate in the sperm acrosome reaction. BBRC 358: 1128-1135.

Schmid, A., Sutto, Z., Nlend, M., Horvath, G., Schmid, N., Buck, J., Levin, L.R., Conner, G., Fregien, N., and Salathe, M. (2007). Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP. J. Gen. Phys. 130: 99-109.

Young, J.J.*, Mehdi, A.*, Stohl, L., Levin, L.R., Buck, J., Wagner, J.A., and Stessin, A.M. (2007). 'Soluble' adenylyl cyclase-generated cyclic AMP promotes fast migration in PC12 cells. J. Neurosci. Res. 86: 118-124.

Schlicker, C., Rauch, A., Hess, K.C., Kachholz, B., Levin, L.R., Buck, J., and Steegborn, C. (2008). Structure-based development of novel adenylyl cyclase inhibitors. J. Med. Chem. 51: 4456-4464.

Ramos, L.*, Zippin, J.H.*, Kamenetsky, M., Buck, J., and Levin, L.R. (2008). Glucose and GLP-1 stimulate cAMP production via distinct adenylyl cyclases in INS-1E insulinoma cells. J. Gen. Physiol. 132: 329-338.

Farrell, J.*, Ramos, L.*, Tresguerres, M., Kamenetsky, M., Levin, L.R., and Buck, J. (2008). Somatic ‘soluble’ adenylyl cyclase isoforms are unaffected in Sacy^tm1Lex/Sacy^tm1Lex ‘knockout’ mice. PLoS ONE 3(9) e3251.

Hallows, K.R., Wang, H., Edinger, R.S., Butterworth, M.B., Oyster, N.M., Li, H., Buck, J., Levin, L.R., Johnson, J.P., and Pastor-Soler, N.M. (2009). Regulation of epithelial Na⁺ transport by soluble adenylyl cyclase in kidney collecting duct cells. JBC 284: 5774-5783.

Acin-Perez, R., Salazar, E., Kamenetsky, M., Buck, J., Levin, L.R., and Manfredi, G. (2009). Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metabolism 9: 265-276.

Tresguerres, M., Parks, S.K., Salazar, E., Levin, L.R., Goss, G.G, and Buck, J. (2009). Bicarbonate-sensing soluble Adenylyl Cyclase is an essential sensor for acid-base homeostasis. PNAS 107:442-447.

Zippin, J.H, Chadwick, P., Levin, L.R., Buck, J., and Magro, C. (2010). Soluble adenylyl cyclase defines a nuclear cAMP microdomain in keratinocyte hyperproliferative skin diseases. J. Investigative Dermatology 130: 1279-1287.

Tresguerres, M, Levin, L.R., Buck, J., and Grosell, M.. (2010). Modulation of NaCl absorption by [HCO3-] in the marine teleost intestine is mediated by soluble adenylyl cyclase. AJP-Regulatory, Integrative and Comparative Physiology 299:R62-R71.

Tresguerres, M, Buck, J.,and Levin, L.R. (2010). Physiological carbon dioxide, bicarbonate and pH sensing. Pflugers Archiv - European Journal of Physiology 460:953-964.

Hall, R.A., De Sordi, L., MacCallum, D.M., Topal, H., Eaton, R., Bloor, J.W., Robinson, G.K., Levin, L.R., Buck, J., Wang, Y., Gow, N.A.R., Steegborn, C., and Muhlschlegel, F.A. (2010). CO2 acts as a signalling molecule in the fungal pathogen Candida albicans. PLoS Pathogens 6(11): e1001193.

Tresguerres, M, Levin, L.R., and Buck, J. (2011). Signaling by Soluble Adenylyl Cyclase. Kidney International 79:1277-1288.

Buck, J. and Levin, L.R. (2011). Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. Sensors 2011 , 11, 2112-2128.

Ramos-Espiritu, L.S., Hess, K.C., Buck, J. and Levin, L.R. (2011). The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms. JPET 338: 925-931.

Acin-Perez, R., Russwurm, M., Gunnewig, K., Gertz, M., Zoidl,G., Ramos, L., Buck, J., Levin, L.R., Rassow, J., Manfredi, G., and Steegborn, C. (2011). A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. JBC 286: 30423-30432.

Hall, R.A., Turner, K.J., Chaloupka, J., Cottier, F, De Sordi, L., Sanglard, D., Levin, L.R., Buck, J, and Muhlschlegel, F. (2011). The quorum sensing molecules Farnesol/Homoserine lactone and Dodecanol operate via distinct modes of action in Candida albicans. Euk Cell 10: 1034-1042.

Lee, Y-S., Tresguerres, M., Hess, K., Marmorstein, L.Y., Levin, L.R., Buck, J., and Marmorstein, A.D. (2011). Regulation of anterior chamber drainage by bicarbonate sensitive adenylyl cyclase in the ciliary body. J. Biol. Chem. 286:41353-8.

Mohammad, S., Ramos, L.S., Buck, J., Levin, L.R., Rubino, F., and McGraw, T.E. (2011). Gastric inhibitory peptide controls adipose insulin sensitivity via activation of CREB and p110beta isoform of PI3 kinase. J. Biol. Chem. 286: 43062-70.

Chen, J., Levin, L.R., and Buck, J. (2011). Role of soluble adenylyl cyclase in the heart. AJP - Heart. : doi:10.1152/ajpheart00701.2011.

Topal, H., Fulcher, N.B., Bitterman, J., Salazar, E., Buck, J., Levin, L.R., Cann, M.J., Wolfgang, M.C., and Steegborn, C. (2012). Crystal Structure and Regulation Mechanisms of the CyaB Adenylyl Cyclase from the Human Pathogen Pseudomonas aeruginosa. J. Mol. Biol. : doi:10.1016/j.jmb.2011.12.045.