Receptor basics

Overview on all the type of receptors

1. The major signal transducer – REceptor BY : FOZIYA KHAN PHARMACOLOGY BRANCH SEM I

2. CONTENTS INTRODUCTION CHARACTERISTICS CLASSIFICATION ION CHANNEL LINKED RECEPTORS G- PROTEIN LINKED RECEPTORS ENZYME LINKED RECEPTORS NUCLEAR RECEPTORS

3. INTRODUCTION What is receptor? A receptor is a protein molecule usually found inside or on the surface of a cell that receives chemical signals from outside the cell. W hen such chemical signals bind to a receptor, they cause some form of cellular/tissue response , e.g. change in the electrical activity of cell. Therefore, a receptor is a protein molecule that recognizes and responds to endogenous chemical signals, e.g. the acetylcholine receptor recognised and responds to its endogenous ligand, acetylcholine .

4. characteristics Participates in transduction of the signal from the external messenger to some component of the metabolic pathway. Has atleast one additional functional site which is altered by ligand binding (allosteric site). Ligand binding to receptors is saturable, resembling Michaelis – Menten kinetics .

5. classification

6. CLASSIFICATION OF CELL SURFACE RECEPTORS

7. ION CHANNEL LINKED RECEPTORS Act through synaptic signaling on electrically excitable cells and convert chemical signals (ligands) to electrical ones. These membrane spanning proteins undergo a conformational change when a ligand binds to them. These ligands can be neurotransmitter, peptide hormones and the molecule that pass through are ions such as sodium or potassium ions which can alter the charge across the membrane. The ion channel, or pores are opened only for a short time, after which the ligand dissociates from the receptor and the receptor is available once again for a new ligand to bind.

8. MECHANISM OF ACTION

9. G-PROTEIN COUPLED RECEPTORS Also called as 1. Seven- (pass) transmembrane domain receptor i.e. 7TM Receptors because they pass through the cell membrane seven times. 2. Heptahelical receptors 3. Serpentine receptors 4. G- Protein linked receptors GPCRs associate with heterotrimeric G- Proteins (green), i.e. G- Protein composed of 3 different subunits: α , β and γ .

10. GPCR located in cell membrane binds extracellular substances and transmits signals from these substances to an intracellular molecule called a G- Protein (Guanine nucleotide binding protein). Example: β - adrenergic receptors which bind Epinephrine. Prostaglandin E2 receptors which bind inflammatory substances called Prostaglandin and Rhodopsin which contains a photo reactive chemical called retinal that respond to the light signals received by rod cells in eye. There are 2 principal signal transduction pathway involving G- Protein linked receptors: CAMP Signal Pathway Phosphatidylinositol Signal Pathway

11. MECHANISM OF ACTION

12. ENZYME LINKED RECEPTORS Also known as a catalytic receptors transmembrane receptor , where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. integral membrane protein possessing both enzymatic catalytic and receptor functions. Upon ligand binding a conformational change is transmitted which activates the enzyme, initiating signaling cascades.

13. CLASSIFICATION OF ENZYME LINKED RECEPTORS Receptor Tyrosine Kinase (RTK) : contains intrinsic tyrosine kinase activity (EGFR, VEGFR) Receptor Serine/ Threonine Kinase : contains intrinsic serine / threonine kinase activity (TGF- β R) Receptor Guanylyl Cyclases : contain intrinsic cyclase activity (ANP) Tyrosine- Kinase associated Receptors : receptors that associate with proteins that have tyrosine kinase activity (Cytokine receptors) Receptor Tyrosine Phosphatases Histidine- Kinase associated Receptor

14. RECEPTOR TYROSINE KINASES (RTKs ) RTK ligands, such as fibroblast growth factor (FGF), epidermal growth factor (EGF), nerve growth factor (NGF) etc. bind as dimers. Ligand binding to RTK monomers results in dimer formation. Receptors possess an intracellular tyrosine kinase domain. Within the dimer the conformation is changed , locking the kinase into an active state. The kinase of one receptor then phosphorylates a tyrosine residue contained in the “activation lip” of the second receptor.

15. This forces the activation lip out of the kinase active site, allowing ATP bind and resulting in enhanced kinase activity. This induces phosphorylation at further tyrosine residues. Phosphotyrosine Is a conserved “docking site” for many intracellular signal transduction proteins that contain SH 2 domains.

16. NUCLEAR RECEPTORS Nuclear receptors are a family of highly conserved transcription in response to small lipophilic compound. Play important role in development, physiology and diseases in humans by regulating gene expression (Protein and Amino acid formation) Estrogen or β - estradiol act upon the nuclear receptor to regulate gene expression for Female Sex Development. Testosterone or Androgens act upon nuclear receptors to regulate gene expression for Male Sex Development.

17. FUNCTIONS OF THE DOMAIN N- terminal domain : harbors AF1 site that binds to other cell specific transcription factors in a ligand- independent way and modifies the binding or activity of the receptor DNA binding domain : Binds to the specific sequences of DNA called hormone response element Hinge region : Connects the DNA binding domain to the ligand binding domain Ligand binding domain : Harbors the AF2 whose action depends upon the bound ligand C- terminal domain : has ability to the transcription

18. MECHANISM OF ACTION CLASS I NUCLEAR RECEPTORS : > Largely steroid receptors > Ligands are mainly steroids > Located in cytoplasm or attached to cytoskeleton or other structures > When ligand binds, form homodimers in the presence of their partners and migrate to nucleus to trigger signal response > A single ligand can regulate a large number of genes

19. CLASS II NUCLEAR RECEPTORS : > Their ligands are mainly lipids > Located in nucleus > They form heterodimers with retinoid X receptors CLASS III NUCLEAR RECEPTORS : > They transduce endocrine signals but function as homodimers

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