Receptor ppt

slides on receptors.

1. RECEPTORS PRESENTED BY- Dr. Aakanksha Priya JR first year Moderator: Dr. Pramod Kr. Manjhi Dept. of Pharmacology AIIMS Patna .

2. OVERVIEW Definition of receptor History of discovery of Receptors Types of Receptor Functions of Receptors Drug-Receptor Interaction Receptor Theory of Drug Action Orphan and Spare Receptors Receptors and diseases. Conclusion.

3. DEFINITION Receptor is defined as a regulatory macromolecule mostly proteins or binding sites located on the surface or inside the effector cell that serves to recognize the ligand/signal molecule/drug and initiate the response to it, but itself has no other functions. e.g. Voltage gated Na channel acts as receptor for local anesthetics.

4. HISTORY JOHN NEWPORT LANGLEY(1905)- COINED THE CONCEPT OF “RECEPTORS ”

5. PAUL EHRLICH GAVE THE CONCEPT OF RECEPTOR-LIGAND COMPLEX .

6. NOBLE PRIZE In 2012, Nobel Prize in Chemistry was awareded to Dr Robert and Dr Brian Kobilka ‘for studies in G-protein-coupled receptors’ (GPCRs).

7. TARGETS FOR DRUGS BINDING There 4 main targets for drug binding- Receptors Ion channels Enzymes Transporters .

8. CLASSIFICATIONS -I The IUPHAR( International union of Pharmacological Science ) system broadly classifies receptors as : Pharmacological ( mediator based e.g. Nor Epinephrine, Insulin) Biochemical (second messenger based e.g. cAMP, PLC) Molecular/structural (subunit composition e.g 5HT1A) Anatomical (Tissue e.g. muscle or ganglionic Ach or cellular e.g. Cell surface or intranuclear).

9. CLASSIFICATIONS-II On the basis of Nature of Transduction(signal transmission) mechanism- 1. TYPE 1- Ligand-gated ion channels 2.TYPE 2- G- protein-coupled 3.TYPE 3- kinase-linked and related receptors 4. TYPE 4- Nuclear receptors

10. LIGAND-GATED ION CHANNELS Also k/a Ionotropic receptors. Location- Cell membrane. Time - miliseconds Function- regulation of flow of ion across the cell membrane by depolarization/hyperpolarization. Example- Fast neurotransmitters e.g. Nicotinic acetylcholine receptors, GABAa , Glycine, 5-HT3 receptor, glutamate (NMDA).

11. MOLECULAR STRUCTURE- The nicotinic acetylcholine receptors consists of a pentameric assembly of four subunits, termed as ∞, β , γ , δ , each of weight 40-58kDa. The pentameric structure(2∞, β , γ , δ ) possesses two acetylcholine binding sites, each lying at the interface between one of the two ∞ subunits. Both must bind acetylcholine molecules in order for receptor to be activated .

12. MECHANISM OF ACTION- The five helices that form the pore are sharply kinked inwards halfway through the membrane , forming a constriction. When two acetylcholine molecules binds to the binding sites, a conformational change occurs in the extracellular part of the receptor. This twists the ∞ subunits, causing the kinked helical segments to swivel out of the way, thus opening the channel.

13. CLINICAL SIGNIFICANCE- IP3 sensitive Ca2+ channels are responsible for release of Ca2+ from ER and this can be blocked by drugs in the treatment of Malignant hyperthermia. The sulfonylurea Receptor “SUR 1” regulate the ATP-dependent K+ channel are prime target of oral hypoglycemic drug in treatment of Type II DM.

14. G PROTEIN-COUPLED RECEPTORS Also k/a metabotropic/7- transmembrane-domain receptors( largest family. Time- seconds They are membrane receptors that are coupled to intracellular effector system primarily via a G protein . G proteins are signal transducers that convey the information that agonist is bound to the receptor from one or more effector proteins.

15. MAIN G PROTEIN –COUPLED RECEPTOR CLASSES CLASS(sequence homology) RECEPTORS A: Rhodopsin Family The largest group. Receptors for most amine neurotransmitters, many neuropeptides, purines etc. B: Secretin/glucagon receptor family Receptor for Peptide hormones including secretin, glucagon, calcitonin. C: Glutamate receptor/calcium sensor family. Small group. GABA B receptor , Ca2+ sensing receptors. D:Frizzled G protein E:Adhesion GPCR

16. Molecular structure of GPCR The first GPCR to be fully characterized was the β -adrenoreceptor, which was cloned in 1986. The GPCR molecule has 7 ∞-helical membrane spanning hydrophobic amino acid segments which run into 3 extracellular and 3 intracellular loops. Two binding sites includes- agonist binding and G protein coupling. The third intracellular loop interacts with G protein.

17. G Protein They are called G protein because of its interaction with the guanine nucleotides i.e GTP and GDP. G protein consists of three subunits- ∞, β , γ . Guanine nucleotide binds to ∞ subunits, which has an enzymatic activity(GTPase), catalyzing the conversion of GTP to GDP .

18. TARGET FOR G PROTEINS The main target for G proteins, through which GPCRs control different aspects of cell functions- Adenylyl cyclase Phospholipase C Ion channels Rho A/ Rho kinase Mitogen-activated protein kinase.

19. Classification of G protein On the basis of subtypes – Subtype Main effector Clinical significance G ∞ s Stimulates adenylyl cyclase, causing increased cAMP formation Activated by cholera toxin G ∞ i Inhibits adenylyl cyclase, decreasing cAMP formation Blocked by pertussis toxin G ∞o Ca2+ inhibitor G q Phospholipase C activation.

20. Mechanism of action of GPCR When an agonist binds to a GPCR, there is a conformational change in the receptor. This causes the ∞ subunit to exchange its bound GDP for GTP. Binding of GTP activates the ∞ subunit and causes it to release both the βγ dimer and the receptor. Both the GTP bound ∞ subunit and the βγ heterodimer become active signaling molecules .

21. KINASES-LINKED RECEPTORS It is a large group of membrane receptors responding mainly to the protein mediators. Location – cell membrane Time - Hours Structure- single transmembrane helix linking extracellular receptor domain to the intracellular domain. M.O.A- 1) Signal transduction involves dimerization of receptors, followed by autophosphorylation of tyrosine residues. Function- They mainly control cell growth and differentiation, and act indirectly by regulating gene transcription.

22. Two important pathways are- 1) The Ras/Raf/Nitrogen-activated protein (MAP) kinase pathway, important in cell division, growth and differentiation. 2) The Jak /stat pathway activated by cytokines, which controls the synthesis and release of many inflammatory mediators. Examples- Insulin, growth factors, cytokine receptors ( tumour necrosis factor receptors{TNF-∞}, pattern recognition receptors(PRRs).

23. NUCLEAR RECEPTORS Location- Intracellular(nucleus) Structure – Monomeric structure with receptor- and DNA binding domain. Time -Hours Function - the liganded receptor complexes initiate change in gene transcription by binding to hormone response elements in gene promoter and recruiting co-activated or co- repressor factors .

24. TYPES OF NUCLEAR RECEPTOR Class 1- present in the cytoplasm, forms dimers in the presence of their ligand, migrate to the nucleus. Ligands are mainly endocrine in nature. Class II – NRs are generally present in the nucleus and form heterodimers with retinoid X receptors. Their ligand are usually lipid e.g. Fatty acids.

25. FUNCTIONS OF RECEPTORS To propagate regulatory signals from outside to inside the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. To amplify the signal. To integrate various extracellular and intracellular regulatory signals. To adapt to short term and long term changes in the regulatory functions and maintain homeostasis.

26. COMMON TERMINOLOGIES USED IN DRUG- RECEPTORS INTERACTION

27. LIGAND Any molecule which attaches selectively to particular receptors or sites.

28. AGONIST Agonist – It is a ligand capable of binding with receptors so as to alter the state thereby eliciting a response. When it binds to the physiological receptors it mimics the endogenous effects . It is of Three types mainly- Full agonist Partial agonist Inverse agonist .

29. FACTORS AFFECTING AGONIST 1) Affinity - it describes the strength with which the agonist combines with the receptors, and 2) Intrinsic activity/Efficacy- it is the ability to produce a response once the receptors are occupied by the agonist. The activity of an agonist depends on the product of affinity and intrinsic activity .

30. FULL AGONIST It is the ligand that increases the activity of the receptor. It produces the maximal response (IA= UNITY) E.g. Morphine which mimics action of endorphins at mu-opioid receptors

31. PARTIAL AGONIST These ligand partially increases the activity of the receptors and produces a submaximal response. It has an intermediate intrinsic activity between 0 to 1 e.g : Buprenorphine is partial agonist at mu-opioid receptor is a safer analgesic than morphine, as it produces less respiratory depression in overdosage.

32. INVERSE AGOINST It combines with receptors producing reduced receptor activity. It has intrinsic activity of 0 to -1. e.g . Beta carbolines is inverse agonist at BZD receptor .

33. ANTAGONISM It is a ligand that combines with the receptor without producing any response and also inhibits the effect of an agonist by impairing the formation of agonist- receptor complex. e.g. Curare block binding sites for acetylcholine Types of antagonism:- Chemical antagonism Pharmacokinetic antagonism Block of receptor-response linkage Physiological antagonism

34. CHEMICAL ANTAGONISM Chemical antagonism refers to the situation where the two substances combine in solution, as a result effect of active drug is lost by chemical reactions/neutralization. E.g. use of chelating agents (Dimercaprol) that bind to the heavy metals.

35. PHARMACOKINETIC ANTAGONISM Pharmacokinetic antagonism refers to the situation where the ‘ antagonist’ effectively reduces the concentration of the active drug at the site of action. i.e Where one drug affects the absorption, metabolism or excretion of the other drug. E.g.: there is reduction in effect of Warfarin when Phenytoin is given because it accelerates hepatic metabolism of warfarin.

36. BLOCK OF RECEPTOR-RESPONSE LINKAGE

37. PHYSIOLOGICAL ANTAGONISM It is used to describe the interaction of two drugs whose opposing actions in the body tend to cancel each other. E.g. Histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while Omeprazole blocks this effect by inhibiting the proton pump.

38. RECEPTOR THEORIES OF DRUG ACTION

39. OCCUPATIONAL THEORY Clark(1937) propounded a theory of drug action based on occupation of receptors by specific drugs and that the pace of a cellular function can be altered by interaction of these receptors with drugs. Intensity of pharmacological effect is directly proportional to the number of receptors.

40. THE TWO-STATE RECEPTORS MODEL It postulates that receptor, regardless of presence or absence of ligand, exists in two different state: the Ra (active ) and Ri (inactive).

41. ORPHAN RECEPTORS An Orphan receptor is an apparent receptor that has similar structure to other identified receptors but whose endogenous ligand has not been identified. E.g. mostly consists of GPCR and nuclear families.

42. SPARE RECEPTORS When only a fraction(1%) of the population of receptors in a system, are needed to produce a maximal effect, then the particular system is said to have spare receptors Example- Adrenaline on β -adrenoreceptors in cardiac muscles .

43. RECEPTORS AND DISEASES The principal mechanism involved in receptors malfunction are- Autoantibodies directed against receptors proteins Mutation in gene encoding receptors, ion channels and proteins involved in signal transduction.

44. MYASTHENIA GRAVIS Myasthenia gravis is a disease of the neuromuscular junction due to autoantibodies that inactivate nicotinic acetylcholine receptors. Autoantibodies mimics the effects of agonists(in case of thyroid hypersecretion), caused by activation of thyrotropin receptors.

45. NEPHROGENIC DIABETES INSIPIDUS Inherited mutations of Gene encoding GPCRs is responsible for causing mutated Vasopressin and adrenocorticotrophic hormones , thus causing ADH resistance Diabetes Insipidus

46. CONCLUSION Receptors are molecules which are essential for majority of biochemical and metabolic processes in the body. Extensive research is being done on receptor pharmacology to find out new class of receptors. Newer drug molecules that target different receptor proteins and alter their physiology are needed to be searched for. Discovery about mechanism of orphan receptors can lead to drug development for the effective treatment of diseases.