Receptors Types and Theories Dr. Sanaa Bardaweel
Some terms in receptor-drug interactions Agonists: drugs that mimic the natural messengers and activate receptors. Antagonist: drugs that block receptors. These compounds still bind to the receptor, but they do not activate it. However, since they are bound, they prevent the natural messenger from binding. Partial agonist: Drug binds to a receptor in order to have an agonist effect. However, it may be binding in such a way that the conformational change induced is not ideal, and the subsequent effects of receptor activation are decreased.
Some terms in receptor-drug interactions Partial agonist activity on ion channel, the generated conformational change is not optimum for maximum opening of ion channel.
Some terms in receptor-drug interactions Inverse agonist: has the same effect as an antagonist in that it binds to a receptor, fails to activate it, and prevents the normal chemical messenger from binding. However, Some receptors (e.g. the GABA2, serotonin and dihydropyridine receptors) are found to have an inherent activity even in the absence of the chemical messenger. They are said to be constitutionally active. An inverse agonist is capable of preventing this activity as well.
Some terms in receptor-drug interactions Desensitization:some drugs bind relatively strongly to a receptor, switch it on, but then subsequently block the receptor after a certain period of time. Thus, they are acting as agonists, then antagonists. The mechanism of how this takes place is not clear, but it is believed that prolonged binding of the agonist to the receptor results in phosphorylationof hydroxyl or phenolicgroups in the receptor.
Some terms in receptor-drug interactions
Some terms in receptor-drug interactions Sensitization: Prolonged exposure of a target receptor to an antagonist may lead the cell to synthesize more receptors to compensate for the receptors that are blocked. This is known to happen when some β-blockers are given over long periods.
Some terms in receptor-drug interactions Tolerance: is a situation where higher levels of a drug are required to get the same biological response. If a drug is acting to suppress the binding of a neurotransmitter, then the cell may respond by increasing the number of receptors. This would require increasing the dose to regain the same level of antagonism.
Theories of drug-receptor interaction Over the years a number of hypothesis have been proposed to account for the ability of a drug to interact with a receptor and elicit a biological response. Starting from the earliest hypothesis, the drug-receptor theories are: 1) Occupancy theory 2) Rate theory 3) Induced-fit theory 4)Macromolecular Perturbation theory 5) Activation-aggregation theory 6) The two-state (multistate) model of receptor activation.
Theories of drug-receptor interaction Occupancy theory States that the intensity of the pharmacological effect is directly proportional to the number of receptors occupied by the drug. The response ceases when the drug-receptor complex dissociates. However, this theory does not rationalize partial agonists and does not explain inverse agonists. The theory was then modified to account for partial against.
Theories of drug-receptor interaction The theory was then modifiedto account for partial agonist, that the drug-receptor interactions involve two stages: 1) There is a complexationof the drug with the receptor, which they both termed the affinity. 2) There is an initiation of a biological effect which termed the intrinsic activity or efficacy. Affinity: is a measure of a capacity of a drug to bind to the receptor, and is dependent on the molecular complementary of the drug and receptor. Efficacy: is the property of a compound that produces the maximum biological response.
Theories of drug-receptor interaction pk d : measure of affinity α: measure of efficacy
Theories of drug-receptor interaction According to modified occupancy theory, a full agonist or partial agonist is said to display positive efficacy, an antagonist displays zero efficacy, and a full or partial inverse against displays negative efficacy (depresses basal tissue response). This theory does not account for why two drugs that can This theory does not account for why two drugs that can occupy the same receptor can act differently, i.e., one as agonist, the other as antagonist.
Theories of drug-receptor interaction
Theories of drug-receptor interaction Rate theory: Suggest that the pharmacological activity is a function of the rate of association and dissociation of the drug with the receptor, and not the number of occupied receptors. In case of agonist: the rates of both association and dissociation would be fast (the later faster than the former). Antagonist: the rate of association with a receptor would be fast, but the dissociation would be slow. Partial agonist: have an intermediate drug-receptor complex dissociation rates. As in the case of occupancy theory, the rate theory does not rationalize why the different types of compounds exhibit the characteristics that they do.
Theories of drug-receptor interaction Induced fit theory: According to this theory the receptor need not necessarily exist in the appropriate conformation required to bind the drug. As the drug approaches the receptor, a conformational change is induced that orients the essential binding sites responsible for the initiation of the biological response. The receptor was suggested to be elastic, and it could return to its original conformation after the drug was released. The conformational change need not occur only in the receptor,; the drug also could undergo deformation, even if this resulted in the strain in the drug.
Receptor activation
Theories of drug-receptor interaction According to this theory, an agonistwould induce a conformational change and elicit a response, an antagonist would bind without a conformational change, a partial agonist would cause a partial conformational change.
Theories of drug-receptor interaction Macromolecular Perturbation Theory This theory suggested that in the interaction of a drug with a receptor two general types of macromolecular perturbations could result: specific conformational perturbation makes possible the binding of certain molecules that produce a biological response (an agonist); nonspecific conformational perturbation accommodates other types of molecules that do not elicit a response (an antagonist). If the drug contributes to both macromolecular perturbations, a mixture of two complexes will result ( a partial agonist) This theory does not address the concept of inverse agonism.
Theories of drug-receptor interaction Activation-Aggregation Theory A receptor is in a state of dynamic equilibrium between an activated form (R o ), which is responsible for the biological response, and an inactive form (T o ). Agonistbind to the R o form and shift the equilibrium to the activated form, antagonists bind to the inactive form (T o ), and partial agonist bind to both conformations. In this model the agonist binding site in the R o conformation can be different from the antagonist binding site in the T o conformation. This theory, however, does not address inverse agonists.
Theories of drug-receptor interaction The Two-Sate (Multisate)Model of Receptor Activation This model propose that, in the absence of the natural ligand or agonist, receptors exist in equilibrium (defined by equilibrium constant L; between an active state (R*) which is able to initiate a biological response, and a resting state (R), which cannot. In the absence of a natural ligand or agonist, the equilibrium between R* and R defines the basal activity of the receptor.
Theories of drug-receptor interaction
Theories of drug-receptor interaction Full agonist binds to the active state and alter the equilibrium to the active state causing maximum response; Partial agonists preferentially bind to the active state, but not to the extend that a full agonist does, so maximum response is not attained; Full inverse agonists bind to the resting state and alter the equilibrium fully to the resting state, causing a negative efficacy; An antagonist have equal affinities for both states (i.e., have no effect on the equilibrium or basal activity, and therefore, exhibit neither positive or negative efficacy)
Receptor types There are four different types (or superfamilies) of receptors: 1) ion channel receptors; give response in milliseconds 2) G-protein-coupled receptors; seconds 3) kinase-linked receptors; minutes 4) Intracellular receptors; hours or days Receptors type 1, 2, and 3 are membrane-bound receptors. Intracellular receptors are not membrane bound.
Ion channel receptors Ion channels are complexes made up of 5 protein subunits which traverse the cell membrane. The centre of the complex is hollow and is lined with polar amino acids to give a hydrophilic tunnel or pore.
Ion channel receptors
Ion channel receptors Small number of neurotransmitter molecules released by a nerve is able to have such a significant biological effect on the target cell. By opening a few ion channels, several thousand ions are mobilized for each neurotransmitter molecule involved (magnified response). Moreover, the binding of a neurotransmitter to an ion channel results in a rapid response, measured in a matter of milliseconds. Ion channels for sodium (Na + ), potassium (K + ), and calcium (Ca2 + ) ions. There are also anionic ion channels for the chloride ion (Cl - ). How they are selective??
Ion channel receptors Structure The protein subunits in an ion channel are not identical. For example, the ion channel controlled by the nicotinic cholinergic receptor is made up of five subunits of four different types (two α, β, γ, δ); the ion channel controlled by the glycinereceptor is made up of five subunits of two different types (3 x α, 2 x β). Alpha subunit is the ligand-binding site for most receptors Each subunit traverses the cell membrane four times. This means that each subunit has four transmembrane(tm) regions which are hydrophobic in nature. These are labelled TM1-TM4. There is also a lengthy N-terminal extracellular chain which (in the case of the α-subunit) contains the ligand-binding site
Ion channel receptors Ion channel controlled by a glycinereceptor. The second transmembrane region of each subunit faces the central pore of the ion channel
Ion channel receptors Gating When the receptor binds a ligand, it changes shape and this has a knock on effect on the protein complex which causes the ion channel to open a process called gating. The lock gate is made up of five kinked α-helices where one helix (the 2-TM region of each subunit). In the closed state the kinks are pointing towards each other. The conformational change induced by ligand binding causes each of these helices to rotate such that the kink points the other way, thus opening up the pore
Gating process Ion channel receptors
G-Protein-coupled receptors G-Protein-coupled receptors 30% of all drugs on the market act by binding to these receptors. They include the muscarinicreceptor, adrenergic receptors and opioidreceptors They are membrane-bound proteins that are responsible for activating proteins called G-proteins. There is a substantial amplificationof the signal in this process, since one activated receptor activates several G- proteins, and the activation of one enzyme by a G-protein subunit results in several enzyme catalyzed reactions.
G-Protein-coupled receptors Structure The G-protein-coupled receptors fold up within the cell membrane such that the protein chain winds back and forth through the cell membrane seven times. Each of the seven transmembrane(7-tm)sections is hydrophobic and helical in shape, and it is usual to assign these helices with roman numerals (I, II etc). The binding site for the G-protein is situated on the intracellular side The binding site for the neurotransmitter or hormone messenger is on the extracellular portion of the protein.
G-Protein-coupled receptors
G-protein-coupled receptors Although G-protein-coupled receptors have similar overall structures, their amino acid sequences vary quite significantly. Therefore, G-protein-coupled receptors are divided into various sub-families which are defined as: class A (rhodopsin-like receptors), class B (secretin-like receptors), and class C (metabotropicglutamate-like and pheromone receptors).
G-protein-coupled receptors Signal transduction pathways for G-protein-coupled receptors G-proteins are membrane-bound proteins situated at the inner surface of the cell membrane and are made up of three protein subunits (α, β, and γ). The α-subunit has a binding pocket which can bind guanyl The α-subunit has a binding pocket which can bind guanyl nucleotides (hence the name G-protein) and which binds guanosinediphosphate(gdp) when the G-protein is in the resting state.
G-protein-coupled receptors Different α-subunits there are at least 20 of them have different targets and different effects: α s as stimulates adenylatecyclase. α i inhibits adenylatecyclaseand may also activate potassium ion channels. α o activates receptors that inhibit neuronal calcium ion channels. α q activates phospholipasec.
Examples: -Activate Lipase -Deactivate Glycogen synthase A
G-protein-coupled receptors G-protein effect on phospholipasec Phosphatidylinositoldiphosphate(PIP2) (an integral part of the cell membrane) generate the two secondary messengers diacylglycerol(dg) and inositol triphosphate(ip3)
G-protein-coupled receptors Hydrophilic 2 nd messenger Hydrophobic
Kinase-linked receptors Kinase-linked receptors are a superfamilyof receptors which activate enzymes directly and do not require a G-protein An important example of kinase-linked receptors are the tyrosine kinasereceptors which are proving to be highly important targets for novel anticancer drugs. The protein concerned plays the dual role of receptor and enzyme. The receptor protein is embedded within the cell membrane, with part of its structure As long as the messenger is bound, the active site remains open and amplify its signal by phosphorylationreactions to take place.
Kinase-linked receptors
Kinase-linked receptors Activation mechanism for tyrosine kinase receptors Epidermal Growth Factor (EGF) receptor as an example
Intracellular receptors There are about 50 members of this group and they are particularly important in directly regulating gene transcription. As a result, they are often called nuclear hormone receptors or nuclear transcription factors. The chemical messengers for these receptors include steroid hormones, thyroid hormones and retinoids.
Intracellular receptors
Intracellular receptors
Spare receptor In many tissues, only a small percentage of the available receptors need to be occupied to produce a maximum response. Therefore, 100% occupancy of the available receptors is not always required, because spare receptors (or a receptor reserve) are present. For example, 5 to 10% of the available α-receptors need to be activated to elicit a maximum response. To obtain a maximum response to a partial agonist like ephedrine, however, nearly 100% of the receptors need to be occupied.