Alan Smrcka

Summary

Affiliation: University of Rochester
Country: USA

Publications

  1. doi request reprint Molecular targeting of Gα and Gβγ subunits: a potential approach for cancer therapeutics
    Alan V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Trends Pharmacol Sci 34:290-8. 2013
  2. pmc Role of phospholipase Cε in physiological phosphoinositide signaling networks
    Alan V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA
    Cell Signal 24:1333-43. 2012
  3. pmc G protein βγ subunits: central mediators of G protein-coupled receptor signaling
    A V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Cell Mol Life Sci 65:2191-214. 2008
  4. pmc G protein betagamma subunits as targets for small molecule therapeutic development
    Alan V Smrcka
    Department of Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Comb Chem High Throughput Screen 11:382-95. 2008
  5. pmc NMR analysis of G-protein betagamma subunit complexes reveals a dynamic G(alpha)-Gbetagamma subunit interface and multiple protein recognition modes
    Alan V Smrcka
    Institute for Research in Biomedicine, Barcelona Science Park, Barcelona, Spain
    Proc Natl Acad Sci U S A 107:639-44. 2010
  6. pmc Rational design of a selective covalent modifier of G protein βγ subunits
    Axel L Dessal
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA
    Mol Pharmacol 79:24-33. 2011
  7. pmc Understanding molecular recognition by G protein βγ subunits on the path to pharmacological targeting
    Yuan Lin
    Department of Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Mol Pharmacol 80:551-7. 2011
  8. pmc Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation
    D M Lehmann
    University of Rochester, Department of Pharmacology and Physiology, 601 Elmwood Ave, Box 711, Rochester, NY 14642, USA
    Mol Pharmacol 73:410-8. 2008
  9. ncbi request reprint Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits
    Tara L Davis
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, MC 9050, Dallas, Texas 75390 9050, USA
    Biochemistry 44:10593-604. 2005
  10. ncbi request reprint Differential targeting of Gbetagamma-subunit signaling with small molecules
    Tabetha M Bonacci
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Science 312:443-6. 2006

Collaborators

  • Barry M Willardson
  • GRANT KELLEY
  • Matthew J Mahon
  • Tabetha M Bonacci
  • Sundeep Malik
  • Mousumi Ghosh
  • Stephen M Lanier
  • Chujun Yuan
  • Motohiko Sato
  • Axel L Dessal
  • Yuan Lin
  • D M Lehmann
  • Joe B Blumer
  • Simona Citro
  • Tara L Davis
  • Ernest Giralt
  • Roger Prades
  • A M P B Seneviratne
  • Emily A Oestreich
  • Julie Radeff-Huang
  • Joan Heller Brown
  • William M Chilian
  • Jennifer L Mathews
  • Jean M Bidlack
  • David M Lehmann
  • Eiji Toyota
  • Jose L Font
  • Dianqing Wu
  • Pamela A Lucchesi
  • Mary J Cismowski
  • Stephen R Sprang
  • Gregory G Tall

Detail Information

Publications20

  1. doi request reprint Molecular targeting of Gα and Gβγ subunits: a potential approach for cancer therapeutics
    Alan V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
    Trends Pharmacol Sci 34:290-8. 2013
    ..Here we will discuss the requirements for targeting Gα and Gβγ subunits, the mechanisms of action of currently identified inhibitors, and focus on the potential utility of Gα and Gβγ inhibitors in the treatment of various cancers...
  2. pmc Role of phospholipase Cε in physiological phosphoinositide signaling networks
    Alan V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642, USA
    Cell Signal 24:1333-43. 2012
    ..These studies together reveal a surprisingly wide range of unexpected functions for PLCε in cellular signaling, physiology and disease...
  3. pmc G protein βγ subunits: central mediators of G protein-coupled receptor signaling
    A V Smrcka
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Cell Mol Life Sci 65:2191-214. 2008
    ..Recent data suggest that Gbetagamma is a potential therapeutic drug target. Thus, a thorough understanding of the molecular and physiological functions of Gbetagamma has significant implications...
  4. pmc G protein betagamma subunits as targets for small molecule therapeutic development
    Alan V Smrcka
    Department of Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Comb Chem High Throughput Screen 11:382-95. 2008
    ..However, further refinement of the approach could significantly improve the yield of Gbetagamma binding molecules from this screen that could result in multiple candidate leads for future drug development...
  5. pmc NMR analysis of G-protein betagamma subunit complexes reveals a dynamic G(alpha)-Gbetagamma subunit interface and multiple protein recognition modes
    Alan V Smrcka
    Institute for Research in Biomedicine, Barcelona Science Park, Barcelona, Spain
    Proc Natl Acad Sci U S A 107:639-44. 2010
    ..Overall, these data show that Gbetagamma subunits explore a range of conformations that can be exploited during molecular recognition by diverse binding partners...
  6. pmc Rational design of a selective covalent modifier of G protein βγ subunits
    Axel L Dessal
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA
    Mol Pharmacol 79:24-33. 2011
    ..These data support the concept that covalent modifiers can be specifically targeted to the Gβγ "hot spot" through rational incorporation into molecules that noncovalently bind to Gβγ...
  7. pmc Understanding molecular recognition by G protein βγ subunits on the path to pharmacological targeting
    Yuan Lin
    Department of Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Mol Pharmacol 80:551-7. 2011
    ..Because each target has a unique recognition mode for Gβγ subunits, it suggests that these interactions could be selectively manipulated with small molecules, which could have significant therapeutic potential...
  8. pmc Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation
    D M Lehmann
    University of Rochester, Department of Pharmacology and Physiology, 601 Elmwood Ave, Box 711, Rochester, NY 14642, USA
    Mol Pharmacol 73:410-8. 2008
    ..Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall, the data demonstrate that targeting Gbetagamma-regulation may be an effective anti-inflammation strategy...
  9. ncbi request reprint Structural and molecular characterization of a preferred protein interaction surface on G protein beta gamma subunits
    Tara L Davis
    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, MC 9050, Dallas, Texas 75390 9050, USA
    Biochemistry 44:10593-604. 2005
    ....
  10. ncbi request reprint Differential targeting of Gbetagamma-subunit signaling with small molecules
    Tabetha M Bonacci
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Science 312:443-6. 2006
    ..These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy...
  11. pmc Mechanistic pathways and biological roles for receptor-independent activators of G-protein signaling
    Joe B Blumer
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112, United States
    Pharmacol Ther 113:488-506. 2007
    ....
  12. pmc Phospholipase Cepsilon is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation
    Simona Citro
    Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 104:15543-8. 2007
    ..Thus, PLCepsilon serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers...
  13. ncbi request reprint Signaling by a non-dissociated complex of G Protein betagamma and alpha subunits stimulated by a receptor-independent activator of G protein signaling, AGS8
    Chujun Yuan
    Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Biol Chem 282:19938-47. 2007
    ..These data implicate a mechanism for AGS8, and potentially other Gbetagamma binding proteins, for directing Gbetagamma signaling through alternative effector activation sites on Gbetagamma in the absence of subunit dissociation...
  14. pmc Identification of a receptor-independent activator of G protein signaling (AGS8) in ischemic heart and its interaction with Gbetagamma
    Motohiko Sato
    Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    Proc Natl Acad Sci U S A 103:797-802. 2006
    ..Mechanistically, AGS8 appears to promote G protein signaling by a previously unrecognized mechanism that involves direct interaction with Gbetagamma...
  15. pmc G-protein-coupled receptor agonists activate endogenous phospholipase Cepsilon and phospholipase Cbeta3 in a temporally distinct manner
    Grant G Kelley
    Department of Medicine and Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
    J Biol Chem 281:2639-48. 2006
    ..Activation of these PLC isoforms displays agonist-specific temporal profiles; however, PLCbeta3 is predominantly involved in acute and PLCepsilon in sustained PI hydrolysis...
  16. ncbi request reprint A docking site for G protein βγ subunits on the parathyroid hormone 1 receptor supports signaling through multiple pathways
    Matthew J Mahon
    Endocrine Unit, Massachusetts General Hospital, Boston, Massachuesetts 02114, USA
    Mol Endocrinol 20:136-46. 2006
    ..Herein, we define a domain on the PTH1R that is capable of binding G protein heterotrimeric complexes via direct Gbetagamma interactions...
  17. ncbi request reprint Ric-8 enhances G protein betagamma-dependent signaling in response to betagamma-binding peptides in intact cells
    Sundeep Malik
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Box 711, Rochester, NY 14642, USA
    Mol Pharmacol 68:129-36. 2005
    ..Overall, these experiments provide further support for the hypothesis that mSIRK promotes G protein subunit dissociation to release free betagamma subunits in intact cells...
  18. ncbi request reprint Regulatory interactions between the amino terminus of G-protein betagamma subunits and the catalytic domain of phospholipase Cbeta2
    Tabetha M Bonacci
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, New York 14642, USA
    J Biol Chem 280:10174-81. 2005
    ....
  19. pmc Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins
    Grant G Kelley
    Department of Medicine, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
    Biochem J 378:129-39. 2004
    ..In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLCepsilon by distinct and overlapping pathways...
  20. ncbi request reprint Assay for G protein-dependent activation of phospholipase C beta using purified protein components
    Mousumi Ghosh
    Department of Pharmacology and Physiology, University of Rochester School of Medicine, NY, USA
    Methods Mol Biol 237:67-75. 2004
    ..It can also be used to assess the functionality of the components after modification by mutagenesis, chemical modification, or in the presence of competing molecules...

Research Grants26

  1. Mechanism for Regulation of Phospholipase C by G Protein
    Alan Smrcka; Fiscal Year: 2005
    ..Given the well known involvement of Ras in mitogenesis and cancer, investigation of this mechanism could yield information about PLC involvement in cancer. ..
  2. STRUCTURAL BASIS FOR BINDING TO G PROTEIN BETA GAMMA
    Alan Smrcka; Fiscal Year: 2007
    ..4. Identification of sites of interaction G protein betagamma subunits with cellular targets using deuterium exchange mass spectrometry. ..
  3. Mechanism for Regulation of Phospholipase C by G Protein
    Alan Smrcka; Fiscal Year: 2007
    ..Elucidation of the functions and mechanisms of this novel Epac/PLCe pathway could lead to novel therapeutic strategies for heart failure, pulmonary disease and hypertension. ..
  4. Mechanism for Regulation of Phospholipase C by G Protein
    Alan Smrcka; Fiscal Year: 2007
    ..Elucidation of the functions and mechanismsof this novel Epac/PLCe pathway could lead to novel therapeutic strategies for heart failure, pulmonary disease and hypertension. ..
  5. Selective Targeting of G Protein beta gamma Subunits with Small Molecules
    Alan V Smrcka; Fiscal Year: 2010
    ..Public Health Relevance: Results of these experiments will help to validate this alternate approach to modification of signaling pathways downstream of GPCRs that could ultimately lead to development of novel therapeutics. ..
  6. Mechanism for Regulation of Phospholipase C by G Protein
    Alan V Smrcka; Fiscal Year: 2010
    ..Elucidation of the functions and mechanisms of this novel Epac/PLCe pathway could lead to novel therapeutic strategies for heart failure, pulmonary disease and hypertension. ..
  7. Nano-HPLC-ESI Quadrupole Ion Trap Mass Spectrometer
    Alan Smrcka; Fiscal Year: 2005
    ..A cost recovery plan will be implemented that will cover costs in future years. ..
  8. SIGNAL TRANSDUCTION BY G PROTEIN
    Alan Smrcka; Fiscal Year: 1999
    ..Finally, oligomerization of PLC and the potential involvement of this process in regulating PLC activity will be investigated by FRET, sucrose density gradient centrifugation, and fluorescence polarization anisotropy. ..
  9. STRUCTURAL BASIS FOR BINDING TO G PROTEIN BETA GAMMA
    Alan Smrcka; Fiscal Year: 2003
    ..IV. Determine the structural basis for these interactions using NMR spectroscopy to solve the 3 dimensional structure of peptides that bind to different surfaces of betagamma subunits. ..
  10. Selective Targeting of G Protein beta gamma Subunits with Small Molecules
    Alan V Smrcka; Fiscal Year: 2010
    ..Public Health Relevance: Results of these experiments will help to validate this alternate approach to modification of signaling pathways downstream of GPCRs that could ultimately lead to development of novel therapeutics. ..