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Cell Signaling: G-Protein Coupled Receptors and the Β

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Cell Signaling: G-Protein Coupled Receptors and the Β Cell Signaling: G-Protein Coupled Receptors and the β2-Adrenergic Receptor Dianna Amasino, Axel Glaubitz, Susan Huang, Joy Li, Hsien-Yu Shih, Junyao Song, Xiao Zhu Madison West High School, Madison, WI 53726 Advisor: Basudeb Bhattacharyya, University of Wisconsin, Madison, WI 53706 Mentors: Dr. Dave Nelson and Peter Vander Velden, University of Wisconsin, Madison, WI 53706 Introduction Mechanism of the β adrenergic receptor: an example of GPCR signal A conserved structure and mechanism G protein-coupled receptors (GPCRs) are the largest transduction family of integral membrane proteins coded by the human genome. GPCRs are important for signal transduction with the general structural characteristic of a plasma membrane receptor with seven transmembrane segments (Figure 1). One example of a GPCR targeted by pharmaceutical companies is the β2-adrenergic receptor. Adrenergic receptors are found through out the body and are triggered by the hormone epinephrine (also known as adrenaline, hence the name adrenergic). When epinephrine binds to the receptors, it causes a slight conformational change within the receptor. This Cherezov, et al., 2007 change then triggers activation of a G-protein, which induces a response within the cell (for example, muscle contraction). When this signal transduction event Figure 4. Overlay of bovine rhodopsin (cyan) and the functions normally in the body, it helps regulate heart rate human β2-adrenergic receptor (orange) and blood pressure and is important for the “fight or Figure 4 above demonstrates how conserved the structure, flight” response. Beta blockers are medically used to and hence the mechannsm, of signal transduction using bind to adrenergic receptors, manipulating the hormone’s GPCRs really is. Rhodopsin, one of the most thoroughly concentration. We have used rapid prototyping studied GPCRs, binds retinal and is needed for vision. technology to model the interaction of the human β2- The two proteins’ active sites line up almost perfectly three adrenergic receptor with the beta blocker, carazolol. By dimensionally, even though the two proteins have modeling the β2-adrenergic receptor, we hope to better seemingly completely different purposes. understand GPCRs as well as understand the mechanism of hormone/drug binding, which will aid in A Pharmaceutical Target developing better drug treatments. Nelson and Cox, 2007 Figure 2. Mode of Action of the β2 adrenergic receptor ¾ Upon binding of the ligand (epinephrine) to the cytosolic face, a conformational change occurs to both the receptor and the G protein (guanine nucleotide binding protein). ¾ The conformational change leads to the exchange of GDP for GTP on the α-subunit of the G protein. ¾ Upon binding of GTP, the α-subunit dissociates and Figure 5. β2-adrenergic receptor bound to the beta binds to its effector protein. The beta and gamma blocker drug carazolol (orange) Cherezov, et al., 2007 subunits facilitate the G-protein transfer and help specify Many human diseases, such as diabetes and the enzyme. hypertension (high blood pressure) are linked to ¾ After some random amount of time, the GTPase activity GPCRs. Determining the structure of GPCRs such Figure 1. General Structure and Location of GPCRs Like that is built into the α-subunit cleaves GTP to GDP. as the β -adrenergic receptor will lead to the all GCPRs, adrenergic receptor has a structure of seven 2 ¾ Cleavage of GTP causes the α-subunit to revert to its development of more effective drug treatments. We alpha-helical transmembrane architecture. The external inactive conformation, to leave its target protein, and to have modeled the interaction between one such drug- signal—the ligand—binds to the receptor and causes it to Nelson and Cox, 2007 re-associate with the β- and γ-subunits. The system thus GPCR interaction. undergo a conformational change. The mechanism, which returns to its resting state. Figure 3. Nobel Prize Winning Research involves the transfer of G proteins, is universally adopted by ¾ In the case of epinephrine, epinephrine binds to its Alfred Gilman and Martin Rodbell won the References all GCPRs. The picture above illustrates the structure of β2- Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi HJ, Kuhn receptor, the conformational change of the receptor 1994 Nobel Prize in Medicine for P, Weis WI, Kobilka BK, and Stevens RC. (2007) High-Resolution Crystal Structure of an adrenergic receptor cross cell membrane. Cholesterol is Engineered Human β -Adrenergic G Protein-Coupled Receptor. Science. 318: 1258-1265. allows it to be coupled to the G protein, which binds to understanding signal transduction through 2 also required for proper functioning of the receptor. Nelson DL and Cox MM. (2007) Lehninger Principles of Biochemistry. 5th Ed. Worth Publishers. adenylate cyclase as its effector protein and activates it. GPCR mechanisms. New York..
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