Roger Sunahara

Professor of Pharmacology

Ph.D., University of Toronto, Canada
Postdoctoral Fellow, University of Texas Southwestern Medical Center

Research Focus: Structure and Function of G Protein-coupled Receptors

Phone: 734.647.6277
E-mail: sunahara@umich.edu
Fax: 734.763.4450

Our laboratory is primarily interested in the elucidation of the molecular mechanism by which hormones activate G protein-Coupled Receptors (GPCRs). We utilize biochemical and biophysical approaches to delineate how hormone binding to these cell surface receptors leads to activation of G proteins. G protein-coupled receptors represent the largest family of membrane proteins in the human genome and the third largest family of genes overall.  Their diversity has made GPCRs the target for greater than 30% of all therapeutics currently on the market.  High-resolution structural and functional analyses of members of the GPCR superfamily will undoubtedly lead to the development of more efficient, more selective and more efficacious therapeutics.  We have recently elucidated the crystal structure of the b2-adrenergic receptor (b2AR) in several conformations, including bound to its cognate G protein, Gs.  The b2AR is a prototypical GPCR and the target of therapeutics used to treat many cardiovascular and smooth muscle ailments.  The b2AR couples to the stimulatory G protein, Gs, which directly activates adenylyl cyclase, the enzyme that converts ATP to cAMP.  Increases in the second messenger cAMP leads to activation of protein kinase A (PKA) among others and modulation of several downstream signaling cascades, including those that regulate transcription of thousands of genes. 

The elucidation of the structure of the GPCR•G protein complex, in particularly, has revealed several novel aspects of G protein structure and function and thus opened up new areas in G protein signaling.  Moreover this novel structural information has for the first time revealed the structure of the activated state a GPCR, a conformation that is induced, or rather stabilized, by agonists such as hormones.  Together these data will provide a new framework with which the design and development of therapeutics may be based.

The goal of our laboratory is to utilize biophysical and biochemical approaches to elucidate the behavior of GPCRs and to determine how receptor conformation may influence the capacity to interact with intracellular signaling partners.  Indeed G proteins represent a major signaling partner for GPCRs however these seven transmembrane domain-containing proteins also potently and actively recruit scaffolding proteins such as arrestins.  In addition to being involved in receptor internalization and desensitization arrestins serve as scaffolding templates to recruit protein kinases including MEKs and Src.  The recruitment of these complexes leads to activation of transcription through the ERK pathway.  Most agonists and hormones activate both the arrestin and G protein signaling cascades.  However, an intriguing phenomena surrounds the capacity of some ligands to stabilize a conformation that recruits arrestin but do not activate G protein-mediated signaling events.  Conversely, there are collections of ligands that potently regulate G protein signaling but do not recruit arrestins.  Thus the study of the molecular bases of the behavior of these ‘biased ligands’ is a major priority in the GPCR field and a major component of our laboratory’s research interests.   It is our aim to utilize biophysical and biochemical approaches to delineate the pharmacological properties of these biased ligands.

Sunahara Research Group


Representative Publications

  1. Whorton, MR, Bokoch, MP, Rasmussen, SGF, Huang, B, Zare, RN, Kobilka, B and Sunahara, RK. A monomeric G protein coupled receptor efficiently couples to its G protein.  Proc. Natl. Acad. Sci. 104(18):7682-7687, 2007.

  2. Whorton, MR, Jastrzebska, B, Park, PS-H, Fotiadis, D, Engel, A, Palczewski, K, and Sunahara, RK. Efficient coupling of transducin to monomeric rhodopsin in a phospholipid bilayer.  J Biol Chem. 283(7):4387-94. Feb 15, 2008.

  3. Yao XJ, Vélez Ruiz G, Whorton MR, Rasmussen SG, DeVree BT, Deupi X, Sunahara RK (Co-corresponding), Kobilka B. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex.  Proc Natl Acad Sci 2009 Jun 9;106(23):9501-6. Epub 2009 May 22.

  4. Kuszak AJ, Pitchiaya S, Anand JP, Mosberg HI, Walter NG, Sunahara RK. Purification and functional reconstitution of monomeric mu-opioid receptors: Allosteric modulation of agonist binding by Gi2. J Biol Chem. J Biol Chem. 2009 Sep 25;284(39):26732-41.

  5. Fung JJ, Deupi X, Pardo L, Yao XJ, Velez-Ruiz GA, Devree BT, Sunahara RK, Kobilka BK. Ligand-regulated oligomerization of beta(2)-adrenoceptors in a model lipid bilayer. EMBO J. 2009 Nov 4;28(21):3315-28. Epub 2009 Sep 17.

  6. Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK.  Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature. 2011 Jan 13;469(7329):175-80.

  7. Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK. Structure and function of an irreversible agonist-β(2) adrenoceptor complex.  Nature. 2011 Jan 13;469(7329):236-40.

  8. Rasmussen SGF, DeVree BT (equal first), Zou Y, Kruse AC, Chung KY, Thian T-S, Thian F-S, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah TSA, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis1 WI, Sunahara RK (Co-corresponding) and Kobilka BK.  Crystal Structure of the b2 Adrenergic Receptor-Gs protein complex, Nature 2011 Sep 28;477(7366):549-555 (cover article).

  9. Chung KY, Rasmussen SGF, Liu T, Li S, DeVree BT, Chae PS, Calinski D Kobilka BK, Woods jr VL, Sunahara RK. b2 adrenergic receptor-induced conformational changes in the heterotrimeric G protein Gs, Nature 2011 Sep 28;477(7366):611-615.

  10. Westfield  G, Rasmussen SGF, Su M, Dutta S, DeVree BT, Chung KY, Calinski D, Velez-Ruiz G, Oleskie AN, Pardon E, Chae PS, Liu T, Li S, Woods jr VL, Steyaert J, Kobilka BK, Sunahara RK (Co-corresponding) and Skiniotis G. Structural rearrangements of the Gαs α-helical domain in the β2-adrenoceptor Gs complex. Proc Natl Acad Sci .2011 Sep 20;108(38):16086-91. Epub 2011 Sep 13.