April 2008 Molecule of the Month by David Goodsell
Keywords: epinephrin, adrenaline, G-protein coupled receptor activity, signal transduction
Our bodies have many built-in defenses. Our immune system prowls through the body looking for infections by viruses and bacteria. Our blood is filled with molecules that form clots at the first sign of damage. Our nervous system is also hard-wired with instinctive defenses that stand ready to protect us in times of danger. You have probably experienced one of these defenses yourself--when you are startled or scared by an impending danger, you will feel a rush of energy flowing through your body. This has been termed the "flight or fight" response--your body is mobilizing its many resources to make you ready either to run away from danger, or stay and fight.
A Cascade of Response
The small hormone adrenaline, also known as epinephrine, is the messenger that tells cells to ready themselves in danger. It is released into the blood from the adrenal glands, which are situated on top of the kidneys. Then it spreads through the blood to cells throughout the body, where it is sensed by adrenergic receptors on the cell surface. When the adrenergic receptor is stimulated by adrenaline, it passes the message inside the cell to a G-protein. The G-protein then relays the message to a variety of other signaling enzymes, such as adenylyl cyclase, that amplify and spread the message through the cell. To see some of the structures involved in this signaling cascade, take a look at the earlier Molecule of the Month on G-proteins.
Feel the Rush
When the body is flooded with adrenaline, we focus all of our energy on the danger at hand. Defensive functions are activated, such as increasing the heart rate and providing more sugar in the blood. Normal housekeeping functions, such as digestion, are temporarily halted as we respond to the challenge. This requires different cells to respond differently to adrenaline--heart cells need to be activated, but cells in the digestive system need to wait for a better time to do their jobs. To orchestrate this range of responses, human cells build nine different types of adrenergic receptors, each with a slightly different effect. The one shown here, the beta-2 adrenergic receptor (PDB entry 2rh1), stimulates cells to increase energy production and utilization. Other types of adrenergic receptors are inhibitory, slowing the use of energy. By expressing one type or another on their surfaces, different cells tailor their responses to adrenaline, making themselves ready for an emergency.
The adrenergic receptors are part of a large class of similar proteins, collectively known as G-protein-coupled receptors, often abbreviated GPCR. These receptors play many diverse and important roles in human health. By some estimates, there are almost a thousand different types in the human genome, including hundreds of receptors for taste and smell. Many widely-used drugs, such as Prozac, Claritin, and Zoloft, act by binding to proteins involved in GPCR signaling. In spite of their importance, they have been extraordinarily difficult to study, since they are normally buried inside a membrane. For many years, the structure of rhodopsin was the only structure available for this class of proteins, and many studies have been performed using rhodopsin as the starting point for structural study of other receptors. This is a successful approach because the receptors are all very similar. They are composed of one chain that snakes back and forth across the membrane seven times. For this reason, they are occasionally also called serpentine receptors. The meandering path of the protein chain is shown here for two GPCR structures: the adrenergic receptor (left, PDB entry 2rh1) and rhodopsin (right, PDB entry 1f88). This illustration was created with the Python Molecule Viewer.
click on the above Jmol tab for an interactive visualization
Exploring the Structure
To solve the structure of the adrenergic receptor, researchers had to
do some unusual things. Since it is normally buried in a cell membrane,
it is difficult to crystallize in purified form. Different approaches
were taken for two structures. In one case, shown on the left from PDB
the protein was engineered to insert lysozyme in the middle of the
chain. The fused protein chain folds normally, with the lysozyme
portion hanging off the bottom of the receptor. In the other case,
shown on the right from PDB entry
an antibody was discovered that binds to the receptor, and the complex
of receptor with antibody was crystallized. In both cases, the extra
protein -- lysozyme or antibody -- helped create the many
protein-protein contacts needed for a stable crystal.
These pictures were created with RasMol. To create similar pictures, you can click on the accession codes here and pick one of the options under Images and Visualization.
Additional reading about adrenergic receptors
D.M. Rosenbaum, V. Cherezov, M.A. Hanson, S.G. Rasmussen, F.S. Thian,
T.S. Kobilka, H.J. Choi, X.J. Yao, W.I. Weis, R.C. Stevens, and
B.K. Kobilka (2007) GPCR engineering yields high-resolution structural
insights into beta2-adrenergic receptor function. Science. 318(5854): 1266-73.
K. M. Small, D. W. McGraw and S. B. Liggett (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Annual Review of Pharmacology and Toxicology 43, 381-411.
S. Takeda, S. Kadowaki, T. Haga, H. Takaesu and S. Mitaku (2002) Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Letters 520, 97- 101.
G. Milligan, P. Svoboda and C. M. Brown (1994) Why are there so many adrenoreceptor subtypes? Biochemical Pharmacology 48, 1059-1071. An interesting short paper about controversy with the names "adrenaline" versus "epinephrine": J. K. Aronson (2000) "Where name and image meet"--the argument for "adrenaline." British Medical Journal 320, 506-509.