Curriculum Vitae
BS George Washington University 1965
Ph.D University of Connecticut 1970
Postdoc. Muscle Biochemistry and Biophysics (with Professor John Gergely) Boston Biomedical Research Institute 1970-1974
Associate in Neurology, Harvard Medical School 1974-1975
Assistant Professor, Department of Cell Biophysics, Baylor College of Medicine 1975-1977
Associate Professor, Department of Pharmacology and Cell Biophysics, University of Cincinnati 1977-1981
Professor, University of Cincinnati, 1981-1983
Professor and Chairman, Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine 1983-present.
THE LABORATORY OF JAMES D. POTTER, Ph.D /
DANUTA SZCZESNA-CORDARY, Ph.D.
Pictured from left-right, front row, Yingcai Wang, Fatima deFreitas, Danuta Szczesna-Cordary (PI), James D. Potter (PI) Michelle Jones, Michelle Parvatiyar, José Renato Pinto; second row, Jiang-Sheng Liang, Zoraida Diaz-Perez, Elba Lalor, Yuhui Wen, Georgianna Guzman, Sherlley Sanon, Sanjeev Sirpal, David Dweck, Hannah Wasserman..
RESEARCH PROJECTS IN THE LABORATORY OF
JAMES D. POTTER, Ph.D.
Personnel: Faculty: James D. Potter, Ph.D.(PI), Danuta Szczesna-Cordary, Ph.D. (PI), Associate Professor, Yingcai Wang, Ph.D., Assistant Professor
 Research Associates: Georgianna Guzman, Michelle Jones, Jiang-Sheng Liang
Postdoctoral Fellows: José Renato Pinto, Ph.D.
Research Staff: Zoraida Diaz-Perez
Graduate Students: Fatima deFreitas, David Dweck, Michelle Parvatiyar, Sanjeev Sirpal, Yu Hui Wen
Undergraduate Students: Sherlley Sanon (University of Miami), Hannah Wasserman (Columbia University)
High School Students: Erin Alexander, Joseph Diaz, Olivia Ordonez
Collaborators: Michael Ackerman, M.D., Ph.D. (Mayo Clinic), Christopher Ashley, Ph.D. (Oxford University), Nanette Bishopric, M.D. (University of Miami), Jonathan Davis, Ph.D. (Ohio State University), Aldrin Gomes, Ph.D. (University of California, Davis), Bjorn C. Knollmann, M.D./Ph.D. (Vanderbilt University), Joseph Metzger, Ph.D., (University of Michigan), Franklyn Prendergast, M.D./Ph.D. (Mayo Clinic), Keith Webster, Ph.D. (University of Miami).
The major theme of the lab’s current research projects is the study of the cellular signaling events associated with the regulation of cardiac and skeletal muscle contraction in normal and pathological states. The lab currently has three NIH grants and a fourth that received a very good priority score and will be funded. The abstracts from these four grants are listed below:
Cardiac Troponin in Health and Disease
The overall goal of the proposed studies is to eluicidate the molecular mechanisms involved in the regulation of cardiac muscle contraction by troponin (Tn) in health and disease. The current proposal will determine the effect of mutations in cTnT, cTnI and cTnC, known to cause familial hypertrophic cardiomyopathy (FHC or HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) on the biochemical, contractile and electrophysiological properties of cardiac muscle. Knock-in mice will be generated expressing cTn subunits that contain mutations known tu cause HCM, DCM and RCM in man and the morphological and in vitro and in vivo properties of these cardiac disease states will be investigated. The following Specific Aims will be pursued: Specific Aim 1: Physiological Consequences of Troponin - Mediated Genetic Disorders Studied in the HCM, DCM, and RCM Mouse Models. We propose to utilize the following knock-in mice (five of these six have already been produced) to study these three types of cardiomyopathy: (A) HCM: cTnI-R21C and cTnT-R92W; (B) DCM: cTnI- D K183 and cTnT-R141W and (C) RCM: cTnI-K178E and cTnI-R145W. We will perform: i) Biochemical characterization; ii) Fiber studies (to establish Ca 2+ sensitivity of ATPase/force and g app); iii) Force and intracellular [Ca 2+] transients; iv) Tissue analysis; and v) Physiological and electrophysiological characterization. Specific Aim 2: Elucidate the Role that Troponin C, A Molecular Ca 2+ Switch Plays in HCM, DCM AND RCM. The following mutant cTnC knock-in mice are proposed for this study: cTnC-S37G (HCM), cTnC-F20Q (DCM) and cTnC-V44Q (RCM). If, as we hypothesize, cTnC is ultimately responsible for the calcium dependent phenotypic properties underlying HCM, DCM and RCM that are caused by the mutations in either cTnC or TnT and/or TnI, one would expect that making these knock-in mutations in cTnC that alter its Ca 2+ binding affinity and/or other contractile properties of muscle, would prodouce phenotypes in proposed knock-in mice that are similar to those seen in man. Specific Aim 3: Analysis of the Physiological Measurements in Aim 1 and 2 will be Utilized to Propose Unifying Theories of Mechanisms Responsible for HCM, RCM and DCM. A comprehensive theory or theories regarding the mechanisms responsible for HCM, DCM and RCM will be proposed. We will evaluate the data and group the results according to various cardiomyopathies. The results will be further analyzed for correlations that deine characteristics of HCM, RCM and DCM. Our multidimensional approach will allow elucidation of the mechanisms that are responsible for specific myopathies and the determination of the severity of specific mutations that cause malignant phenotypes and SCD in man. These studies will be critical in understanding the effect these genetic structural changes have on cardiac muscle and how they might lead to the three distinctive disease states.
Physiological Role of the Myosin Regulatory Light Chains
The long-term goal of the proposed studies is to determine the roles of skeletal muscle myosin light chains, the RLC (LC2, regulatory) and the ELC (LC1 and LC3, essential), in muscle development, regulation and/or modulation of contractile function. Our working hypotheses are: 1) Lack of skeletal myosin RLC or ELC prevents the development of the muscle type associated with that particular light chain; 2) Ca 2+ and/or Mg 2+ binding to the single Ca 2+-Mg 2+ binding site on the fast and slow skeletal RLC is required for muscle formation and proper function; 3) The phosphorylation of Ser 16 in RLC plays an important role in RLC-mediated regulation and/or modulation of contraction; 4) The long isoform ECL1 and short isoform ECL3 play different physiological roles in the regulation of muscle contraction. To test the above hypotheses and to pursue our studies we are proposing the following: Specific Aim 1: Function of the fast and slow skeletal RLC during muscle development in transgenically “rescued” RLC-f knock-out mice. A generation of slow skeletal transgenic (Tg) mice utilizing the KO mice. B. Characterization of the RLC-s expression pattern in embryonic, neonatal and adult Tg-mice. C. Physiological measurements in skinned and intact muscle preparations from RLC-s Tg-mice. Specific Aim 2: The importance of the RLC (fast and/or slow) Ca 2+ binding site in the development and regulation of striated muscle function. A. Generate RLC-s Tg-mice containing an inactivated Ca 2+ binding site (D49A). B. Generation of RLC-f D49E knock-in (KI) mice (increased Ca 2+ affinityi and specificity). Specific Aim 3: Contractile properties and Ca 2+ dependent force development in RLC-f S16A (constitutively unphosphorylated) and RLC-f S16D (constitutively phosphorylated) KI mice. A. Generation of RLC-f S16A KI mice. B. Generation of RLC-f S16D KI mice. Specific Aim 4: Functional properties of the fast skeletal muscle containing myosin composed of the coil-coiled heavy chain, RLC and: A. exclusively fast skeletal ELC1 or B. exclusively ELC3. A. Generation of ELC1 KI mice with exclusion of ELC3. B. Generation of ELC3 KI mice with exclusion of ELC1. In summary, our studies on the slow skeletal RLC transgenic and RLC mutant and ELC1/3 knock-in mice will provide new insights into the role of the regulatory and the essential light chains, respectively in the regulation and/or modulation of skeletal muscle contraction.
The Function of Slow Skeletal TnT in Muscle Contraction
The overall goal of the proposed experiments is to determine the molecular mechanisms involved in the regulation of slow skeletal muscle contraction by troponin T (TnT) and to determine what regions of TnT are important for its physiological function. To accomplish this overall goal we will carry out two specific aims: Specific Aim 1. The Role Of Slow Skeletal Troponin T Isoforms In The Regulation Of Muscle Contraction. Essentially nothing is known about the regulation of slow skeletal muscle by troponin T (TnT) and this is the prime focus of our study which will thoroughly investigate the function of slow skeletal muscle TnT (SSTnT) in the regulation of striated muscle contraction. The main hypothesis to be tested here is that the various N-terminal SSTnT isoforms modulate Ca2+-sensitivity and the relaxation properties of slow skeletal muscle contraction. We will answer the following questions: 1) Is the Ca2+-sensitivity of force development and/or ATPase activity affected by the N- or C-terminal regions of SSTnT? 2) Do SSTnT isoforms directly affect the affinity of TnC for Ca2+ or is there an indirect effect of SSTnT on the Ca2+ sensitivity of contraction (e.g., thin filament or crossbridge effect)? 3) Do the different SSTnT isoforms interact differently with tropomyosin? 4) Do SSTnT isoforms affect the activation and relaxation of force in skinned muscle fibers? 5) Are there other isoforms of SSTnT that have not been previously described? These studies will determine the role of the N-and C-terminal alternatively spliced regions of SSTnT on slow skeletal muscle contraction. Specific Aim 2. The Role Of Different Regions Of Slow Skeletal Troponin T In The Physiological Function Of Troponin T. To understand the role of different regions of TnT we will carry out the following: 1) Characterization of the region of SSTnT that is important for Ca2+-independent ATPase activity. 2) Characterization of the region(s) of SSTnT that interacts with SSTnI, CTnC (same isoform in slow skeletal and cardiac muscle) and tropomyosin. 3) Investigation of the importance of SSTnI in the function of SSTnT. No functional studies on any region of SSTnT have so far been reported. All the Specific Aims listed above focus on gaining a more detailed understanding of the role of SSTnT in slow skeletal muscle contraction, including the molecular mechanisms of SSTnT-linked activation of muscle contraction.
Recent References
Szczesna, D., Zhang, R., Zhao, J., Jones, M. and Potter, J.D.: The Role of the NH2- and COOH-terminal Domains of the Inhibitory Region of TnI in the Regulation of Skeletal Muscle Contraction. J. Biol. Chem., 274:1999, pp.29536-29542.
Lipscomb, S., Palmer, R.E., Li, Q., Allhouse, L.D., Miller, T., Potter, J.D., and Ashley, C.C.: A Diazo-2 Study of Relaxation Mechanisms in Frog and Barnacle Muscle Fibres: effects of pH, MgADP, and Inorganic Phosphate. Pflugers Arch. 437:1999, pp. 204-212.
Pan, B-S., Housmans, P.R., Hannon, J.D., Wiedmann, R., Potter, J.D., Kranias, E.G., Shen, Y-T., and Johnson, Jr., R.G., Housmans, P.R. Effects of Isoproterenol on Twitch Contraction of Wild Type and Phospholamban-Deficient Murine Ventricular Myocardium. J. Mol. Cell Cardiol.31:1999, pp. 159-166.
Allhouse, L.D., Potter, J.D. and Ashley, C.C: A Novel Method of Extraction of TnC from Skeletal Muscle Myofibrils. Pflugers Arch (Eur. J. Physiol) 437:1999, pp.695-701.
Moncrieffe, M.C., Eaton, S., Bajzer, Z., Haydock, C., Prendergast, F.G., Potter, J.D. and Laue, T.M.: Rotational and Translational Motion of Troponin C. J. Biol. Chem., 274:1999, pp.17464-17470.
Allhouse, L.D., Guzman, G., Miller, T., Potter, J.D., Li, Q. and Ashley, C.C.: Characterisation of a Mutant of Barnacle Troponin C Lacking Ca2+ Binding Sites at Positions II and IV. Pflugers Arch. (European J. Physiol.) 438:1999, pp.30-39.
Cates, M.S., Berry, M.B., Ho, E.L., Li, Q., Potter, J.D., and Phillips, G.N.: Metal Ion Affinity and Specificity in EF-Hand Proteins: Coordination Geometry and Domain Plasticity in Parvalbumin. Structure Fold Des 7:1999, pp.1269-1278.
Moncrieffe, M.C., Venyaminov, S.Y., Miller, T.E., Guzman, G., Potter, J.D., and Prendergast, F.G.: Optical Spectroscopic Characterization of Single Tryptophan Mutants of Chicken Skeletal Troponin C: Evidence for Inter-domain Interaction. Biochemistry 38:1999, pp.11973-11983.
Szczesna, D., Zhang, R., Zhao, J., Jones, M., Guzman, G. and Potter, J.D.: Altered Regulation of Cardiac Muscle Contraction by Troponin T Mutations that Cause Familial Hypertrophic Cardiomyopathy. J. Biol. Chem. 276: 2000, 624-30.
Moncrieffe, M.C., JuranR c, N., Kemple, M.D., Potter, J.D., Macura, S. and Prendergast, F.G. Structure Fluorescence Correlations in a Single Tryptophan Mutant of Carp Parvalbumin: Solution Structure, Backbone and Sidechain Dynamics. J.Mol. Biol. 297: 2000, 147-63.
Allhouse, L.D., Guzman, G., Li, Q., Miller, T., Lipscomb, S., Potter, J.D., and Ashley, C.C. Investigating the Role of Ca2+-binding Site IV in Barnacle Troponin C. Pflugers Arch. 439: 2000, 600-9.
Kischel, P., Bastide, B., Potter, J.D. and Mounier, Y. The Role of the Ca2+ Regulatory Sites of Skeletal Troponin C in Modulating Muscle Fibre Reactivity to the Ca2+ Sensitizer Bepridil. Br. J. Pharmacol. 131: 2000, 1496-502.
Szczesna, D., Ghosh, D., Li, Q., Gomes, A.V., Guzman, G., Arana, C., Zhi, G., Stull, J.T., Potter, J.D. Abnormal Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding and phosphorylation. J. Biol. Chem. 276: 2001, 7086-92.
Miller, T., Szczesna, D., Housmans, P.R., Zhao, J., de Freitas, F., Gomes, A.V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W.G. and Potter, J.D. Abnormal Contractile Function in Transgenic Mice Expressing an FHC-Linked Troponin T (I79N) Mutation. J. Biol. Chem. 276: 2001, 3743-55.
Knollmann, B.C., Groth, A., Horton, K., de Freitas, F., Miller, T., Bell, M., Morad, M., Weissman, N.J., and Potter, J.D. Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy. J. Biol. Chem. 276: 2001, 10039-48.
Christenson, R.H, Duh, S.H., Apple, F.S., Bodor, G.S., Bunk, D.M., Dalluge, J., Panteghini, M., Potter, J.D., Welch, M.J.,Wu, A.H, and Kahn, S.E. Standardization of cardiac troponin I assays: round Robin of ten candidate reference materials. Clin. Chem. 47: 2001, 431-7.
Hernandez, O.M., Housmans, P.R., and Potter, J.D. Invited Review: pathophysiology of cardiac muscle contraction and relaxation as a result of alterations in thin filament regulation. J. Appl. Physiol. 90: 2001, 1125-36.
Harada, K., Arana, C., and Potter, J.D. Magnesium-calcium exchange with the high affinity Ca2+-Mg2+ binding sites of cardiac troponin. J Mol Cell Cardiol 33: 2001, 593-6.
Knollmann B.C. and Potter J. D. Altered Regulation of Cardiac Muscle Contraction by Troponin T Mutations that cause Familial Hypertrophic Cardiomyopathy. Trends Cardiovascular Medicine 11:2001, 206-12.
Szczesna, D. and Potter, J.D.: The Role of Troponin in the Ca2+-Regulation of Skeletal Muscle Contraction. Results Probl Cell Differ 36;2002, 171-90.
Szczesna, D., Jones, M., Zhao, J., Zhi, G., Stull, J.T. and Potter, J.D. Phosphorylation of the Regulatory Light Chains of Myosin Affects Ca2+ Sensitivity of Skeletal Muscle Contraction. J. Appl. Physiol. 92:2002, 1661-70.
Lang, R., Gomes, A.V., Zhao, J., Miller, T., Housmans, P.R. and Potter, J.D. Functional Analysis of a Troponin I Mutation Associated with Hypertrophic Cardiomyopathy. J. Biol. Chem., 277:2002, 11670-8.
Gomes, A.V., Harada, K., and Potter, J.D. Cation Signaling in Striated Muscle Contraction. R. Solaro and R.L. Moss (eds), Molecular Control of Mechanisms in Striated Muscle Contraction. Klumer Academic Publishers. 2002, 163-197.
Gomes, A.V., Potter, J.D. The role of troponins in muscle contraction. IUBMB Life 54:2002, 322-33.
Gomes, A.V., Guzman, G., Zhao, J., Potter, J.D. Cardiac troponin T isoforms affect the Ca2+ sensitivity and inhibition of force development. Insights into the role of troponin T isoforms in the heart. J. Biol. Chem. 277;2002, 35341-9.
Knollmann, B.C., Kirchhof, P., Sirenko, S.G., Degen, H., Greene, A.E., Schober, T., Mackow, J.C., Fabritz, L, Potter, J.D., Morad, M. Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling. Circ. Res. 92;2003, 428-36.
Venkatraman, G., Harada, K., Gomes, A.V., Kerrick, G.W., Potter, J.D. Different functional properties of Troponin T mutants that cause dilated cardiomyopathy . J. Biol. Chem. 278; 2003, 41670-41676.
Harada, K., Potter, J.D. FHC Mutations from Different Functional Regions of Troponin T Result in Different Effects on the pH- and Ca2+- Sensitivity of Cardiac Muscle contraction . J. Biol. Chem. 279; 2004, 14488-14495.
Gomes, A.V., Potter, J.D. Molecular and Cellular Aspects of Troponin Cardiomyopathies. Ann. New York Acad. Sci. 1015; 2004, 214-224.
Gomes, A.V. and Potter, J.D. Cellular and Molecular Aspects of Familial Hypertrophic Cardiomyopathy caused by Mutations in the Cardiac Troponin I Gene. Mol. & Cell. Biochem., 263:99-114, 2004.
Gomes, A.V., Barnes, J.A., Harada, K. and Potter, J.D.The Role of Troponin T in Disease. Mol. & Cell. Biochem., 263:115-129, 2004.
Gomes, A.F., Venkatraman, G. Davis, J.P., Tikunova, S.B., Engel, P., Solaro, R.J. and Potter, J.D.Cardiac Troponin T Isoforms affect the Ca 2+ Sensitivity of Force Development in the presence of Slow Skeletal Troponin I: Insights into the Role of Troponin T isoforms in the Fetal Heart.
J. Biol. Chem., 279 (48):49579-49587, 2004
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Blunt, B.C., Chen, Y., Potter, J.D. and Hoffman, P.A. Modest actomyosin energy conservation increases myocardial postischemic function. Amer. J. of Phys.288:H1088-H1096, 2005.
Dweck, D., Reyes-Alfonso, Jr., A. and Potter, J.D. Expanding the Range of Free Calcium Regulation in Biological Solutions. Analytical Biochem:303-15, 2005.
Gomes, A.V., Harada, K. and Potter, J.D. A mutation in the N-terminus of Troponin I that is associated with Hypertrophic cardiomyopathy affects the Ca2+-sensitivity phosphorylation kinetics and proteolytic susceptibility of troponin. J. Mol. & Cell. Card. 39:754-65, 2005.
Hernandez, O., Szczesna-Cordary, D., Miller, T., Zhao, J., Knollmann, B.C., Sirenko, S.G., Diaz, Z., Guzman, G., Xu, Y., Wang, Y., Kerrick, W.G.L. and Potter, J.D. F1101 and R278C Troponin T Mutations that Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers. J. Biol. Chem. 280:37183-37194, 2005
Chang, A.N., Harada K., Ackerman, and Potter, J.D. Functional Consequence of Familial Hypertrophic and Dilated Cardiomyopathy Causing Mutations in α-Tropomyosin. J. Biol. Chem. 280:34343-34349, 2005
Gomes, A.V., Liang, J. and Potter, J.D. Mutations in Human Cardiac Troponin I that are associated with Restrictive Cardiomyopathy affect basal ATPase Activity and the Calcium Sensitivity of Force Development. J. Biol. Chem. 280:30909-30915, 2005.
Venkatraman, G., Gomes, A.V., Kerrick, G.W. and Potter, J.D. Characterization of Troponin T Dilated Cardiomyopathy Mutations in the Fetal Troponin Isoform.
J. Biol. Chem.280:17584-17592, 2005.
Blunt, B.C., Chen, Y., Potter, J.D. and Hofmann, P.A. Modest actomyosin energy conservation increases myocardial postischemic function.
Amer. J. of Phys.288:H1088-H1088-1096, 2005.
Westermann, D., Knollmann, B.C., Steendijk, P., Potter, J.D., Schultheiss, H-P and Tschöpe, C. Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy. Eur. J. Heart Fail. 8:115-21, 2006.
Sirenko, S.G., Potter, J.D. and Knollmann, B.C. Differential Effect of Troponin T Mutations on the Inotropic Responsiveness of Mouse Hearts – Role of Myofilament Ca2+ Sensitivity Increase. (In Press), 2006.
Gomes, A.V., Miller, T., Zhao, J. Lee, K. Farkas, B. and Potter, J.D. Predicting the Clinical Phenotype of Hypertrophic Cardiomyopathy Patients with Troponin Mutations. Circ. Res. (In Revision) 2006.
Wang, Y., Szczesna-Cordary, D., Craig, R., Diaz-Perez, Z., Guzman, G., Miller, T. and Potter, J.D. Fast Skeletal Muscle Regulatory Light Chain is Required for Fast and Slow Skeletal Muscle Development. (In Press), 2006.
Tikunova, S.B., Alionte, C., Gomes, A.V., Potter, J.D. and Davis, J.P. Effect of Cardiac Troponin C Mutations on Calcium Binding and Exchange with the Troponin Complex and Muscle Force Generation. Biochem. (Submitted), 2006.
Rodenbaugh, D., Wang, W., Davis, J., Edwards, T., Potter, J.D. and Metzger, J. Parvalbumin Isoforms Differentially Accelerate Cardiac Myocyte Relaxation Kinetics in an Animal Model of Diastolic Dysfunction. Am J Phys. (In Press), 2007.
Tikunova, S.B., Alionte, C., Gomes, A.V., Potter, J.D. and Davis, J.P. Effect of Cardiac Troponin C Mutations on Calcium Binding and Exchange with the Troponin Complex and Muscle Force Generation. Biochem. (Submitted), 2006.
Wang, Y., Xuy, Y., Wang, Y., Diaz-Perez, Z., Potter, J.D., Solaro, R.J. and Kerrick, W.G.L. Slow Skeletal Muscle TNI in Mouse Heart: Modeling the Effects of Increased Ca2+ Sensitivity on Cardiac Function. J. Biol Chem. (Submitted), 2007.
Chang, A.N., Greenfield, N., Jones, M. and Potter, J.D. Structural and Protein Interaction Effects of Hypertrophic and Dilated Cardiomyopathic Mutations in α-Tropomyosin. J. Biol. Chem. (Submitted), 2007.
Shen, X., Franzini-Armstrong, C., Jones, L.R., Kobayashi, Y.M., Wang, Y., Kerrick, W.G.L., Caswell, A.H., Potter, J.D., Miller, T., Allen, P.D. and Perez, C.F. Null mutation for triad-associated Triadins does not abolish excitation-contraction coupling in skeletal muscle. J. Cell Biol. (Submitted), 2007.
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