MOD-1.2-RECEPTOR-PHYSIOLOGY.pdf

HUMAN PHYSIOLOGY AND PATHOPHYSIOLOGY MODULE 1.2: RECEPTOR PHYSIOLOGY  TOPIC OUTLINE TOPIC OUTLINE: 1. Receptors 2. Types of Receptors 3. Agonism and Antagonism 4. Receptor Responses  RECEPTORS I...

HUMAN PHYSIOLOGY AND PATHOPHYSIOLOGY MODULE 1.2: RECEPTOR PHYSIOLOGY  TOPIC OUTLINE TOPIC OUTLINE: 1. Receptors 2. Types of Receptors 3. Agonism and Antagonism 4. Receptor Responses  RECEPTORS Is a protein molecule usually found embedded within the plasma membrane surface that receives signals from outside the cell and when such chemical signals bind, they cause some form of cellular/tissue response L I G A N D : a n i o n o r m o l e c u l e wh i c h d o n a t e s a p a i r o f e l e c t r o n s t o t h e c e n t r a l a t o m o r i o n to form a coordination complex Comes from a Latin word means “tie or bind” Ligands can be anions, cations, and neutral molecules Xenobiotics: An example of a ligand that is foreign to the body; a compound not made by the body  RECEPTORS S p e c i f i c m o l e c u l e s i n a b i o l o g i c s y s t e m wi t h wh i c h d r u g s i n t e r a c t t o p r o d u c e changes in the function of the system Must be selective in their ligand-binding characteristics Must be modified when ligand binds to bring a functional changes Mostly are proteins RECEPTOR SITES OR RECOGNITION SITES Specific binding region of the macromolecule High and selective affinity for the drug molecule EFFECTORS Translate ligand-receptor interaction into a change in cellular activity Some receptors are also effectors A single molecule may incorporate both the ligand binding site and the effector mechanism  CLASSIFICATIONS OF RECEPTORS There are 2 types of receptors. Those are: Internal and Cell surface receptors A. INTERNAL / INTRACELLULAR / CYTOPLASMIC RECEPTORS: Found in the cytoplasm of the cell Respond to hydrophobic ligand molecules INTRACELLULAR RECEPTORS Hydrophobic signaling molecules typically diffuse across the plasma membrane Interact with intracellular receptors in the cytoplasm  CLASSIFICATIONS OF RECEPTORS There are 2 types of receptors. Those are: Internal and Cell surface receptors B. CELL-SURFACE / TRANSMEMBRANE RECEPTORS / CELL- SPECIFIC PROTEINS Performs signal transduction, converting an extracellular signal into an intracellular signal Three main components: 1. An external ligand-binding domain (extracellular domain) 2. A hydrophobic membrane-spanning region, 3. And an intracellular domain inside the cell  CLASSIFICATIONS OF RECEPTORS There are 2 types of receptors. Those are: Internal and Cell surface receptors B. CELL-SURFACE / TRANSMEMBRANE RECEPTORS / CELL- SPECIFIC PROTEINS C E L L S U R F A C E R E C E P T O R: - there are three general categories of cell-surface receptors: 1. Ion channel-linked receptors 2. G-protein-linked receptors, 3. Enzyme-linked receptors  ION CHANNEL-LINKED RECEPTORS Receptors bind with ligand. (ex. Nicotinic receptor) O p e n a c h a n n e l t h r o u g h t h e m e m b r a n e t h a t a l l o ws s p e c i f i c i o n s t o p a s s through Conformational change in the protein’s structure that allows ions such as Na, Ca, Mg, H2 to pass through  ENZYME-LINKED RECEPTORS Cell surface receptors with intracellular domains that are associated with an enzyme Normally have large extracellular and intracellular domains When a ligand binds to the extracellular domain, a signal is transferred through the membrane and activates the enzyme, which eventually leads to a response Ex. Tyrosine Kinase receptor  G-PROTEIN LINKED RECEPTORS Binds with a ligand and activate a membrane protein called a G-protein The activated G-protein then interacts with either an ion channel or an enzyme in the membrane Each receptor has its own specific extracellular domain and G-protein binding sites Example: Beta-adrenergic receptor DEFINITION OF TERMS: ADENYLYL CYCLASE - a membrane bound enzyme that catalyzes the conversion of ATP to cAMP (produces cAMP) cAMP - cyclic adenosine monophosphate - a derivative of adenosine triphosphate and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway - a secondary messenger G-PROTEIN LINKED RECEPTORS  G-PROTEIN LINKED RECEPTORS THREE TYPES OF G-PROTEIN RECEPTORS: 1. Gs receptor - a stimulative G protein that activates the enzyme adenylyl cyclase Mechanics: 1. ligand binding in the receptor binding site 2. G p r o t e i n c o u p l e d r e c e p t o r wi l l b e a c t i v a t e d ( G D P - > G T P ) 3. a l p h a - s u b u n i t wi l l d e t a c h t o t h e m a i n r e c e p t o r a n d b i n d t o a d e n y l y l c y c l a s e 4. adenylyl cyclase will produce cAMP  G-PROTEIN LINKED RECEPTORS THREE TYPES OF G-PROTEIN RECEPTORS: 2. Gi receptor - an inhibitory G protein that inhibits adenylyl cyclase, thus lower the level of cAMP in the cell Mechanics: 1. ligand binding in the receptor binding site 2. G p r o t e i n c o u p l e d r e c e p t o r wi l l b e a c t i v a t e d ( G D P - > G T P ) 3. a l p h a - s u b u n i t wi l l d e t a c h t o t h e m a i n r e c e p t o r a n d b i n d t o a d e n y l y l c y c l a s e t o inhibit its action 4. no cAMP will be produced  G-PROTEIN LINKED RECEPTORS THREE TYPES OF G-PROTEIN RECEPTORS: 3. Gq receptor - activates a class of enzyme called phospholipase C (PLC) Mechanics: 1. ligand binding in the receptor binding site 2. G protein coupled receptor will be activated (GDP -> GTP) 3. alpha-subunit will detach to the main receptor and bind to phospholipase C 4. P L C p r o d u c e s t w o s e c o n d a r y m e s s e n g e r s c a l l e d d i a c y l g l y c e r o l ( D A G ) a n d i n o s i t o l t r i p h o s p h a t e ( I P 3) DAG : just like cAMP leads to different responses through activation of protein kinases IP3 : produces various responses by mediating intracellular release of calcium  FORCES AFFECTING LIGAND-RECEPTOR BINDING 3 major types of chemical forces/bonds: Covalent, Electrostatic and Hydrophobic A. COVALENT BOND Very strong “irreversible” undergoing biological conditions Extremely stable Example: It is formed between the activated form of Phenoxybenzamine and the alpha-adrenergic receptor Phenoxybenzamine – a medication used in the management and treatment of paroxysmal hypertension and sweating resulting from pheochromocytoma  FORCES AFFECTING LIGAND-RECEPTOR BINDING 3 major types of chemical forces/bonds: Covalent, Electrostatic and Hydrophobic B. ELECTROSTATIC BOND Very common and weaker than covalent bond Interaction strength is variable Example: Van-der Waals forces  FORCES AFFECTING LIGAND-RECEPTOR BINDING 3 major types of chemical forces/bonds: Covalent, Electrostatic and Hydrophobic C. HYDROPHOBIC INTERACTIONS Generally weak, but important Significant in driving interactions Lipophilic compounds and the lipid component of biological membranes LIGAND-RECEPTOR INTERACTIONS There are two types: agonism and antagonism  AGONISTS There are three types: full, partial and inverse A. FULL AGONIST Capable of fully activating the effector system when it binds to the receptor High affinity for the activated receptor conformation Sufficiently high concentrations result in all the receptors achieving the activated state  AGONISTS There are three types: full, partial and inverse B. PARTIAL AGONIST Produces less than the full effect, even when it has saturated the receptors In the presence of an agonist, a partial agonist acts as an inhibitor/antagonist Example: Morphine + Naloxone  AGONISTS There are three types: full, partial and inverse C. INVERSE AGONIST If a ligand has a much stronger affinity to the Ri conformation than Ra state and stabilizes a large fraction in the Ri-D complex The ligand will reduce any constitutive activity thus resulting in effects opposite of the effects produced by the full agonist E x a m p l e : G A B A- r e c e p t o r e f f e c t o r s  ANTAGONISTS There are three types: competitive, non -competitive, allosteric, physiologic, and chemical A. COMPETITIVE OR REVERSIBLE ANTAGONIST Binds to receptors in a reversible way without activating the effector system Shifts the response curve to the right but the same maximal effect is reached Effects overcome by adding more agonist (surmountable) E x a m p l e : B e t a - b l o c k e r s ( P r o p r a n o l o l ) a n d B e t a- a g o n i s t ( I s o p r o t e r e n o l )  ANTAGONISTS There are three types: competitive, non -competitive, allosteric, physiologic, and chemical B. NON-COMPETITIVE OR IRREVERSIBLE ANTAGONIST Causes downward shift in the response curve No horizontal shift of response curve unless spare receptors are present Not overcome by adding more agonist (insurmountable) Example: Norepinephrine and Phenoxybenzamine  ANTAGONISTS There are three types: competitive, non -competitive, allosteric, physiologic, and chemical C. PHYSIOLOGIC ANTAGONIST Binds to a different receptor producing an effect opposite to that produced by the drug it is antagonizing Example: Histamine and Epinephrine; Propranolol and Thyroid hormone  ANTAGONISTS There are three types: competitive, non -competitive, allosteric, physiologic, and chemical D. CHEMICAL ANTAGONIST Interact directly with the drug being antagonized to remove it or to prevent it from reaching its target Does not depend on interaction with agonist receptors Example: Dimercaprol for lead poisoning; Pralidoxime for organophosphate poisoning  ANTAGONISTS There are three types: competitive, non -competitive, allosteric, physiologic, and chemical E. ALLOSTERIC ANTAGONIST Binds to a different binding sites that forms a conformational change in the receptor preventing the agonist to bind  VARIATIONS IN RECEPTOR RESPONSE TOLERANCE Continuous activation may lead to depletion of essential substrate Reverse by repletion of missing substrates  VARIATIONS IN RECEPTOR RESPONSE TACHYPHYLAXIS Responsiveness diminishes rapidly after administration of a ligand Frequent or continuous exposure to agonists often results in short-term diminution of the receptor response  VARIATIONS IN RECEPTOR RESPONSE DOWNREGULATION Long term reduction in receptor number due to continuous exposure to agonist  VARIATIONS IN RECEPTOR RESPONSE UPREGULATION Occurs when receptor activation is blocked for prolonged period of time E ND O F D ISCU SSIO N