Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 312 (5772): 443-446

Copyright © 2006 by the American Association for the Advancement of Science

Differential Targeting of Gß{gamma}-Subunit Signaling with Small Molecules

Tabetha M. Bonacci,1 Jennifer L. Mathews,1 Chujun Yuan,2 David M. Lehmann,1 Sundeep Malik,1 Dianqing Wu,3 Jose L. Font,1 Jean M. Bidlack,1 Alan V. Smrcka1,2*

Abstract: G protein ß{gamma} subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gß{gamma} subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gß{gamma} subunit functions. Several compounds bound to Gß{gamma} subunits with affinities from 0.1 to 60 µM and selectively modulated functional Gß{gamma}-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor–dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein–coupled receptor signaling that may represent an important therapeutic strategy.

1 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
2 Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
3 Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.

* To whom correspondence should be addressed. E-mail: Alan_Smrcka{at}URMC.rochester.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Expanding Roles of G{beta}{gamma} Subunits in G Protein-Coupled Receptor Signaling and Drug Action.
S. M. Khan, R. Sleno, S. Gora, P. Zylbergold, J.-P. Laverdure, J.-C. Labbe, G. J. Miller, and T. E. Hebert (2013)
Pharmacol. Rev. 65, 545-577
   Abstract »    Full Text »    PDF »
Inhibition of the Ethanol-induced Potentiation of {alpha}1 Glycine Receptor by a Small Peptide That Interferes with G{beta}{gamma} Binding.
L. San Martin, F. Cerda, V. Jimenez, J. Fuentealba, B. Munoz, L. G. Aguayo, and L. Guzman (2012)
J. Biol. Chem. 287, 40713-40721
   Abstract »    Full Text »    PDF »
Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism.
X. Li, J. Shan, W. Chang, I. Kim, J. Bao, H.-J. Lee, X. Zhang, V. T. Samuel, G. I. Shulman, D. Liu, et al. (2012)
PNAS 109, 11402-11407
   Abstract »    Full Text »    PDF »
ARF6 Activated by the LHCG Receptor through the Cytohesin Family of Guanine Nucleotide Exchange Factors Mediates the Receptor Internalization and Signaling.
V. Kanamarlapudi, A. Thompson, E. Kelly, and A. Lopez Bernal (2012)
J. Biol. Chem. 287, 20443-20455
   Abstract »    Full Text »    PDF »
Understanding Molecular Recognition by G protein {beta}{gamma} Subunits on the Path to Pharmacological Targeting.
Y. Lin and A. V. Smrcka (2011)
Mol. Pharmacol. 80, 551-557
   Abstract »    Full Text »    PDF »
Regulators of G-Protein Signaling and Their G{alpha} Substrates: Promises and Challenges in Their Use as Drug Discovery Targets.
A. J. Kimple, D. E. Bosch, P. M. Giguere, and D. P. Siderovski (2011)
Pharmacol. Rev. 63, 728-749
   Abstract »    Full Text »    PDF »
G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease.
S. L. Belmonte and B. C. Blaxall (2011)
Circ. Res. 109, 309-319
   Abstract »    Full Text »    PDF »
A Critical Role of G{beta}{gamma} in Tumorigenesis and Metastasis of Breast Cancer.
X. Tang, Z. Sun, C. Runne, J. Madsen, F. Domann, M. Henry, F. Lin, and S. Chen (2011)
J. Biol. Chem. 286, 13244-13254
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase-Dependent Antagonism in Mammalian Olfactory Receptor Neurons.
K. Ukhanov, D. Brunert, E. A. Corey, and B. W. Ache (2011)
J. Neurosci. 31, 273-280
   Abstract »    Full Text »    PDF »
Rational Design of a Selective Covalent Modifier of G Protein {beta}{gamma} Subunits.
A. L. Dessal, R. Prades, E. Giralt, and A. V. Smrcka (2011)
Mol. Pharmacol. 79, 24-33
   Abstract »    Full Text »    PDF »
Regulation of Constitutive Cargo Transport from the trans-Golgi Network to Plasma Membrane by Golgi-localized G Protein {beta}{gamma} Subunits.
R. Irannejad and P. B. Wedegaertner (2010)
J. Biol. Chem. 285, 32393-32404
   Abstract »    Full Text »    PDF »
Small Molecule Disruption of G{beta}{gamma} Signaling Inhibits the Progression of Heart Failure.
L. M. Casey, A. R. Pistner, S. L. Belmonte, D. Migdalovich, O. Stolpnik, F. E. Nwakanma, G. Vorobiof, O. Dunaevsky, A. Matavel, C. M. B. Lopes, et al. (2010)
Circ. Res. 107, 532-539
   Abstract »    Full Text »    PDF »
Involvement of PLC-{beta}3 in the effect of morphine on memory retrieval in passive avoidance task.
E. Bianchi, D. Lehmann, E. Vivoli, M. Norcini, and C. Ghelardini (2010)
J Psychopharmacol 24, 891-896
   Abstract »    PDF »
G{beta}{gamma} Signaling Promotes Breast Cancer Cell Migration and Invasion.
J. K. Kirui, Y. Xie, D. W. Wolff, H. Jiang, P. W. Abel, and Y. Tu (2010)
J. Pharmacol. Exp. Ther. 333, 393-403
   Abstract »    Full Text »    PDF »
NMR analysis of G-protein {beta}{gamma} subunit complexes reveals a dynamic G{alpha}-G{beta}{gamma} subunit interface and multiple protein recognition modes.
A. V. Smrcka, N. Kichik, T. Tarrago, M. Burroughs, M.-S. Park, N. K. Itoga, H. A. Stern, B. M. Willardson, and E. Giralt (2010)
PNAS 107, 639-644
   Abstract »    Full Text »    PDF »
Blockade of Ethanol-Induced Potentiation of Glycine Receptors by a Peptide That Interferes with G{beta}{gamma} Binding.
L. Guzman, G. Moraga-Cid, A. Avila, M. Figueroa, G. E. Yevenes, J. Fuentealba, and L. G. Aguayo (2009)
J. Pharmacol. Exp. Ther. 331, 933-939
   Abstract »    Full Text »    PDF »
Mice lacking the G protein {gamma}3-subunit show resistance to opioids and diet induced obesity.
W. F. Schwindinger, B. M. Borrell, L. C. Waldman, and J. D. Robishaw (2009)
Am J Physiol Regulatory Integrative Comp Physiol 297, R1494-R1502
   Abstract »    Full Text »    PDF »
Inhibition of Heterotrimeric G Protein Signaling by a Small Molecule Acting on G{alpha} Subunit.
M. A. Ayoub, M. Damian, C. Gespach, E. Ferrandis, O. Lavergne, O. De Wever, J.-L. Baneres, J.-P. Pin, and G. P. Prevost (2009)
J. Biol. Chem. 284, 29136-29145
   Abstract »    Full Text »    PDF »
Differential Inhibitor of G{beta}{gamma} Signaling to AKT and ERK Derived from Phosducin-like Protein: EFFECT ON SPHINGOSINE 1-PHOSPHATE-INDUCED ENDOTHELIAL CELL MIGRATION AND IN VITRO ANGIOGENESIS.
M. L. Guzman-Hernandez, A. Vazquez-Macias, J. Carretero-Ortega, R. Hernandez-Garcia, A. Garcia-Regalado, I. Hernandez-Negrete, G. Reyes-Cruz, J. S. Gutkind, and J. Vazquez-Prado (2009)
J. Biol. Chem. 284, 18334-18346
   Abstract »    Full Text »    PDF »
GIV is a nonreceptor GEF for G{alpha}i with a unique motif that regulates Akt signaling.
M. Garcia-Marcos, P. Ghosh, and M. G. Farquhar (2009)
PNAS 106, 3178-3183
   Abstract »    Full Text »    PDF »
Activation of Leukemia-associated RhoGEF by G{alpha}13 with Significant Conformational Rearrangements in the Interface.
N. Suzuki, K. Tsumoto, N. Hajicek, K. Daigo, R. Tokita, S. Minami, T. Kodama, T. Hamakubo, and T. Kozasa (2009)
J. Biol. Chem. 284, 5000-5009
   Abstract »    Full Text »    PDF »
A selective G{beta}{gamma}-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol.
G. E. Yevenes, G. Moraga-Cid, R. W. Peoples, G. Schmalzing, and L. G. Aguayo (2008)
PNAS 105, 20523-20528
   Abstract »    Full Text »    PDF »
A Novel G{beta}{gamma}-Subunit Inhibitor Selectively Modulates {micro}-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence.
J. L. Mathews, A. V. Smrcka, and J. M. Bidlack (2008)
J. Neurosci. 28, 12183-12189
   Abstract »    Full Text »    PDF »
Small Molecule Disruption of G Protein {beta}{gamma} Subunit Signaling Inhibits Neutrophil Chemotaxis and Inflammation.
D. M. Lehmann, A. M. P. B. Seneviratne, and A. V. Smrcka (2008)
Mol. Pharmacol. 73, 410-418
   Abstract »    Full Text »    PDF »
Signaling by a Non-dissociated Complex of G Protein {beta}{gamma} and {alpha} Subunits Stimulated by a Receptor-independent Activator of G Protein Signaling, AGS8.
C. Yuan, M. Sato, S. M. Lanier, and A. V. Smrcka (2007)
J. Biol. Chem. 282, 19938-19947
   Abstract »    Full Text »    PDF »
Subunit Dissociation and Diffusion Determine the Subcellular Localization of Rod and Cone Transducins.
D. H. Rosenzweig, K. S. Nair, J. Wei, Q. Wang, G. Garwin, J. C. Saari, C.-K. Chen, A. V. Smrcka, A. Swaroop, J. Lem, et al. (2007)
J. Neurosci. 27, 5484-5494
   Abstract »    Full Text »    PDF »
Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function.
T. Zhao, P. Nalbant, M. Hoshino, X. Dong, D. Wu, and G. M. Bokoch (2007)
J. Leukoc. Biol. 81, 1127-1136
   Abstract »    Full Text »    PDF »
Pharmacology. Hitting the hot spots of cell signaling cascades..
J. J. G. Tesmer (2006)
Science 312, 377-378
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882