Cellular receptors: a new step towards the development of selective drugs
Researchers at Stanford University School of Medicine have taken the first step towards developing a new method of finding drugs with fewer side effects.
In an article published online in the journal Nature (Michael P. Bokoch et al., Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor), scientists led by Professor Brian Kobilka report that some areas of cell membrane proteins, for the most part, do not included in the sphere of interests of researchers, in fact, undergo certain structural changes in response to the action of drugs. This feature of surface molecules may be important for the development of new drugs.
A class of proteins known as G-protein coupled receptors (GPCR) is already extremely important in drug research: they are affected in one way or another by almost 40% of all currently existing drugs. In the field of interests of Professor Kobilka's laboratory is one of the types of GPCR, adrenergic receptors activated by adrenaline and its closest relative norepinephrine. These hormones are secreted by the adrenal glands and some nerve cells and regulate key physiological processes in the nervous system, as well as in the muscles and heart. It is they who provide a "fight or flight" reaction in a stressful situation, forcing a person to perform incredible feats, from defeating a saber-toothed tiger to chasing a departing bus.
Like all GPCR receptors, adrenergic receptors include three components. One of them is attached to the cell membrane, the second protrudes from the outer surface of the membrane into the intercellular space, and the third is immersed in the cytoplasm.
The surface receptors of a cell are like a door lock, triggering only when they coincide with the configuration of their active center of the structure of the ligand molecule ("key"). For adrenergic receptors, such a magic key is adrenaline or norepinephrine. If another molecule with a similar structure falls on the adrenergic receptor, it sits on a specific site of the receptor, called the binding pocket, the shape and charge of which perfectly match the shape of the molecule, which ensures a tight fit. The binding pocket of the adrenergic receptor is located on the outer part attached to the cell membrane. Binding of the ligand to the receptor causes a change in the structure of the receptor, allowing the G-protein to attach to its intracellular part. This attachment is the first link in the mechanism of restructuring of biochemical processes in the cell.
In addition to adrenaline and norepinephrine, other molecules are also able to integrate into the binding pockets of adrenergic receptors. This principle underlies many effective medicines. The cell's surface receptors are excellent targets for small molecules capable of stimulating or blocking any physiological process. Different drugs can have completely different effects on the same receptor. Agonist drugs have an affinity for the receptor and translate it into an active or even hyperactive state. Antagonists put the receptor into an inactive state – in much the same way as a badly forged key stuck in a lock.
Adrenergic receptors are represented by nine different subtypes, all of them react to adrenaline or norepinephrine, but play a different role in the regulation of body functions. For example, beta-2 adrenergic receptors relax smooth muscles, in particular, the respiratory tract. Drugs belonging to the class of beta-2 agonists that activate these receptors are used to combat asthma attacks.
The increase in the frequency and strength of heart contractions is primarily due to beta-1 receptors. Their increased activity can lead to serious problems, including heart failure. Therefore, patients with coronary heart disease, heart failure and arrhythmia are often prescribed beta-1 antagonists (or beta blockers).
The trouble is that drugs that affect the receptors of one subtype, at the same time, may be suitable for the receptors of another subtype. Beta-1 and beta-2 receptors mostly react to drugs in the same way, which often causes side effects. Suppose a patient suffers from asthma, and at the same time he has a heart condition. If you try to cure asthma with beta-2 agonists, they can act on beta-1 receptors in the heart, which will lead to arrhythmia. Therefore, this patient cannot use either beta-2 agonists or beta-1 antagonists that can exacerbate asthma.
Although the binding pockets of various subtypes of adrenergic receptors are almost identical, some areas of their extracellular parts have undergone certain changes in the course of evolution. The extracellular domains of beta-1 and beta-2 adrenergic receptors, for example, are completely different. Drugs that are able to selectively attach to the extracellular part of the receptors of only one subtype, while changing the conformation of the cytoplasmic part in the same way as drugs embedded in the binding pockets of the receptor do, may be more selective, with a minimum of side effects.
Professor Kobilka and his colleagues used a very sensitive method of nuclear magnetic resonance to focus their attention on a specific site of the extracellular domain of the beta-2 adrenergic receptor, and to check whether it is possible to detect subtle structural changes under the influence of various drugs.
The scientists tested three drugs: an agonist and an antagonist of the beta-2 receptor, as well as a drug that has no effect on the state of receptor activity. As expected, the ligand molecules fell into the corresponding binding pocket, but at the same time, each drug changed the conformation of the extracellular part of the receptor differently. This suggests that conformational shifts in this part of the receptor are caused by the action of drugs on the corresponding binding pockets.
If this effect is reversible, the molecules binding to the extracellular part of the receptor, in turn, are able to modulate their function. A huge variety of extracellular domain structures can be used to regulate the functions of receptors with a high degree of selectivity.
Even if the "tail wagging dog" effect is insignificant, drugs that target the extracellular surface of GPCR receptors will still not prevent ordinary molecules from embedding into their binding pockets. Thus, instead of simply turning on/off the activity of the receptors, they can become a tool for fine-tuning this activity itself, like a rheostat. From the point of view of medicine, this method of regulating the activity of receptors is simply great.
Ruslan Kushnir
Portal "Eternal youth" http://vechnayamolodost.ru based on Stanford School of Medicine: Research on rarely studied cell-receptor regions opens door to eliminating drugs' side effects18.01.2010