The Expanding Roles of Gbg Subunits in G Protein–Coupled Receptor Signaling and Drug Action
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1521-0081/65/2/545–577$25.00 http://dx.doi.org/10.1124/pr.111.005603 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:545–577, April 2013 Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ERIC L. BARKER The Expanding Roles of Gbg Subunits in G Protein–Coupled Receptor Signaling and Drug Action Shahriar M. Khan, Rory Sleno, Sarah Gora, Peter Zylbergold, Jean-Philippe Laverdure, Jean-Claude Labbé, Gregory J. Miller, and Terence E. Hébert Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (S.M.K., R.S., S.G., P.Z., G.J.M., T.E.H.); Institut de Recherche en Immunologie et en Cancérologie, (J.-P.L., J.-C.L.), and Department of Pathology and Cell Biology (J.-C.L.), Université de Montréal, Montréal, Québec, Canada; and Department of Chemistry, Catholic University of America, Washington, DC (G.J.M.) Abstract ...................................................................................546 Downloaded from I. Introduction . ..............................................................................546 II. Diversity and Phylogeny of Gbg Subunits . ................................................546 A. Gb and Gg Subunits in Lower Eukaryotes ..............................................547 B. Invertebrate Gbg ......................................................................549 C. Plant Gbg .............................................................................550 pharmrev.aspetjournals.org D. Fish and Mammalian Gbg .............................................................550 E. Structural Features of Gbg Subunits . ................................................551 III. Canonical Signaling Regulated by Gbg Subunits . ..........................................552 A. Kir3 Channels . ........................................................................553 B. Voltage-Dependent Ca2+ Channels......................................................554 C. Adenylyl Cyclase Isoforms. ............................................................555 D. Phospholipase C .......................................................................555 E. Phosphoinositide 3 Kinases. ............................................................556 by guest on February 23, 2016 F. Mitogen-Activated Protein Kinases .....................................................557 IV. Noncanonical Effectors of Gbg Signaling . ................................................557 A. Gbg Effects on Cell Division and the Cytoskeleton . .....................................557 B. Gbg Signaling in Cellular Organelles . ................................................558 1. Endosomal Signaling . ............................................................558 2. Mitochondria .......................................................................558 3. Endoplasmic Reticulum . ............................................................558 4. Golgi Apparatus . ..................................................................559 C. Gbg Effects in the Nucleus and Regulation of Transcriptional Activity . 560 V. Other Effectors ............................................................................561 VI. Phenotypes Associated with Knockout and Knockdown of Gb and Gg Subunits. 561 A. Gb Subunit Knockout and Knockdown Models ..........................................561 1. Gb1-4 ...............................................................................561 2. Gb5.................................................................................562 B. Gg Subunit Knockdown and Knockout Models ..........................................563 1. Gg1.................................................................................563 2. Gg2.................................................................................564 This work was supported by grants from the Canadian Institutes of Health Research (CIHR; MOP-79354 to T.E.H.). T.E.H. holds a Chercheur National Award from the Fonds de la Recherche en Santé du Québec. G.J.M. holds a New Investigator Award from the CIHR. R.S., S.M.K., and P.Z. hold scholarships and S.G. holds a postdoctoral fellowship from the McGill-CIHR Drug Development Training Program. Institut de Recherche en Immunologie et en Cancélogie is supported in part by the Canadian Center of Excellence in Commercialization and Research, the Canada Foundation for Innovation, and the Fonds de la recherche en santé du Québec. Address correspondence to: Dr. Terence E. Hébert, Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 1303, Montréal, Québec, H3G 1Y6, Canada. E-mail: [email protected] S.M.K. and R.S. contributed equally to this work. dx.doi.org/10.1124/pr.111.005603. 545 546 Khan et al. 3. Gg3.................................................................................564 4. Gg7.................................................................................564 C. Phenotypic Changes Due to Gbg Polymorphisms and Mutations . 565 VII. Assembly of Gbg Subunits .................................................................566 A. Cytosolic Chaperonin Complex/Phosducin-Like Protein 1 and Its Role in Gbg Assembly. 566 B. Specificity of Gbg Assembly ............................................................568 C. Dopamine Receptor Interacting Protein 78 and Its Role in Gbg Assembly . 568 D. Assembly of Gb5 with Regulator of G Protein Signaling Proteins . 569 VIII. Pharmacological Targeting of Gbg Subunits ................................................570 A. Gbg and the Emergence of the “Hot Spot” ..............................................570 B. Small-Molecule Interference of Gbg Signaling ..........................................571 IX. Conclusion and Future Directions ..........................................................571 References . ..............................................................................572 Abstract——Gbg subunits from heterotrimeric G understanding these expanded roles in different proteins perform a vast array of functions in cells cellular organelles. We suggest that the particular with respect to signaling, often independently as well content of distinct Gbg subunits regulates cellular as in concert with Ga subunits. However, the epony- activity, and that the granularity of individual Gb mous term “Gbg” does not do justice to the fact that and Gg action is only beginning to be understood. 5Gb and 12 Gg isoforms have evolved in mammals Given the therapeutic potential of targeting Gbg to serve much broader roles beyond their canonical action, this larger view serves as a prelude to more roles in cellular signaling. We explore the phyloge- specific development of drugs aimed at individual netic diversity of Gbg subunits with a view toward isoforms. I. Introduction subsequently revealed that Gbg subunits can also modulate many other effectors, via direct interaction, Heterotrimeric G proteins composed of Ga and Gbg that are also regulated by Ga subunits, including subunits relay signals from G protein–coupled recep- phospholipase Cb (Camps et al., 1992), adenylyl cyclase tors (GPCRs) to a wide range of downstream effectors, isoforms (Tang and Gilman, 1991), and voltage-gated including adenylyl cyclase isoforms, phospholipase calcium channels (Ikeda, 1996; Zamponi et al., 1997). In isoforms, ion channels, protein tyrosine kinases, and this review, we focus on the diversity of Gb and Gg mitogen-activated protein kinases (MAPKs), among subunits, their unique roles in the regulation of both bg others. Originally, the G dimer was thought to be canonical and novel effectors, their implications in a necessary primarily for inactivation of G subunits, disease, and their potential as therapeutic targets. In allowing them to reassociate with the receptor for addition to work described here, a number of other subsequent rounds of signaling. In this sense, Gbg was recent reviews focus on different aspects of Gbg function viewed as a negative regulator of Ga signaling, and in greater detail, especially in the context of the G was thought to decrease the signal-to-noise ratio by protein heterotrimer (Smrcka, 2008; Lin and Smrcka, preventing spontaneous Ga activation in the absence of 2011) and GPCR signaling and ontogeny (Dupré et al., receptor stimulation [reviewed in Neer (1995)]. The 2006, 2009; Robitaille et al., 2009a). first evidence for a direct role of Gbg dimers in cellular signaling came in 1987, when it was shown that II. Diversity and Phylogeny of Gbg Subunits purified Gbg subunits from bovine brain were able to activate a cardiac potassium channel normally acti- The presence of diverse, yet sequence-similar Gb and vated by muscarinic receptors following acetylcholine Gg subunits may be the result of an evolutionary release (Logothetis et al., 1987). A large body of work process reflecting the emergence of distinct functions. ABBREVIATIONS: AC, adenylyl cyclase; AEBP1, adipocyte enhancer-binding protein; AP-1, activating protein-1; b2AR, b2-adrenergic receptor; BRET, bioluminescence resonance energy transfer; CCT, cytosolic chaperonin complex; CGS-21680, 3-[4-[2-[[6-amino-9- [(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid; CK2, casein kinase 2; DPDPE, [D-Pen2,D-Pen5]-Enkephalin; DRiP78, dopamine receptor interacting protein 78; ER, endoplasmic reticulum; ERK1/2, extracellular signal- regulated kinase 1/2; GFP, green fluorescent protein; GGL, Gg2like; GPCR, G protein–coupled receptor; GR, glucocorticoid receptor;