Download Adrenergic Receptor

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
G protein-coupled receptors (GPCRs) are the largest
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
change then triggers activation of a G-protein, which
induces a response within the cell (for example, muscle
contraction). When this signal transduction event
functions normally in the body, it helps regulate heart rate
and blood pressure and is important for the “fight or
flight” response. Beta blockers are medically used to
bind to adrenergic receptors, manipulating the hormone’s
concentration. We have used rapid prototyping
technology to model the interaction of the human β2adrenergic receptor with the beta blocker, carazolol. By
modeling the β2-adrenergic receptor, we hope to better
understand GPCRs as well as understand the
mechanism of hormone/drug binding, which will aid in
developing better drug treatments.
Mechanism of the β adrenergic receptor: an example of GPCR signal
transduction
A conserved structure and mechanism
Cherezov, et al., 2007
Figure 4. Overlay of bovine rhodopsin (cyan) and the
human β2-adrenergic receptor (orange)
Figure 4 above demonstrates how conserved the structure,
and hence the mechannsm, of signal transduction using
GPCRs really is. Rhodopsin, one of the most thoroughly
studied GPCRs, binds retinal and is needed for vision.
The two proteins’ active sites line up almost perfectly three
dimensionally, even though the two proteins have
seemingly completely different purposes.
A Pharmaceutical Target
Nelson and Cox, 2007
Figure 2. Mode of Action of the β2 adrenergic receptor
Cherezov, et al., 2007
Figure 1. General Structure and Location of GPCRs Like
all GCPRs, adrenergic receptor has a structure of seven
alpha-helical transmembrane architecture. The external
signal—the ligand—binds to the receptor and causes it to
undergo a conformational change. The mechanism, which
involves the transfer of G proteins, is universally adopted by
all GCPRs. The picture above illustrates the structure of β2adrenergic receptor cross cell membrane. Cholesterol is
also required for proper functioning of the 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
binds to its effector protein. The beta and gamma
subunits facilitate the G-protein transfer and help specify
the enzyme.
¾ After some random amount of time, the GTPase activity
that is built into the α-subunit cleaves GTP to GDP.
¾ Cleavage of GTP causes the α-subunit to revert to its
inactive conformation, to leave its target protein, and to
re-associate with the β- and γ-subunits. The system thus
returns to its resting state.
¾ In the case of epinephrine, epinephrine binds to its
receptor, the conformational change of the receptor
allows it to be coupled to the G protein, which binds to
adenylate cyclase as its effector protein and activates it.
Nelson and Cox, 2007
Figure 3. Nobel Prize Winning Research
Alfred Gilman and Martin Rodbell won the
1994 Nobel Prize in Medicine for
understanding signal transduction through
GPCR mechanisms.
Figure 5. β2-adrenergic receptor bound to the beta
blocker drug carazolol (orange)
Many human diseases, such as diabetes and
hypertension (high blood pressure) are linked to
GPCRs. Determining the structure of GPCRs such
as the β2-adrenergic receptor will lead to the
development of more effective drug treatments. We
have modeled the interaction between one such drugGPCR interaction.
References
Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi HJ, Kuhn
P, Weis WI, Kobilka BK, and Stevens RC. (2007) High-Resolution Crystal Structure of an
Engineered Human β2-Adrenergic G Protein-Coupled Receptor. Science. 318: 1258-1265.
Nelson DL and Cox MM. (2007) Lehninger Principles of Biochemistry. 5th Ed. Worth Publishers.
New York.