receptors.pptx and its types and mechanism

Different receptor types and structure of them

1. Subject : A dvanced pharmacology Types of receptors By : G krishna sri M pharm 1 st year Department of pharmacology

2. Definition : Receptors are class of cellular macromolecules that are concerned specifically and directly with chemical signaling between and within cells . Receptors are the sensing elements in the syste chemical communications that coordinates the function o the different cells in the body, the chemical messengers being various hormones, transmitters and other mediators

3. Affinity :The capability of a drug to form the complex (Drug Receptor Complex) with its receptor. Intrinsic activity : The ability of a drug to trigger the pharmacological response after making the drug-receptor complex . Agonist – These are the drugs which have both high affinity as well as high intrinsic activity. Antagonist : These are the drugs which have only the affinity but no intrinsic activity

4. Drug intercation with receptors : Usually most of drug receptor intercations are reversible with weak chemical bonds Irreversible interactions are less common and undesirable . These are strong chemical bonds The concept of dual nature of receptors Receptors usually exists in two conformations The active (Ra) state Inactive ( Ri ) state If Ra and Ri conframations are in equlibrium , the extent to which this equilibrium perturbed shall be determined by the relative affinity of the drug for these two conframations

5. Agonist -These drugs have high affinity for the active conformation (Ra) than for inactive ( Ri ) Antagonist -These drugs bind to either of these conformations (Ra & Ri ) with equal affinity. It will not shift the equilibrium to any side Partial agonist -These have slightly higher affinity for Ra than for Ri and hence shift the eqaulibrium toward Ra to a lesser extent than true agonist.Such drugs therefore display an intermediate effectiveness between the agonist and antagonist Inverse agonist- There are certain receptors which remain inherently in the Ra state even in the absence of an endogenous ligand or an exogenous agonist.Inverse agonists inactivate such constitutively active receptors and therefore prevent its basal activity. • As a result inverse agonist produce an effect opposite to that of an agonist / drug even in its absence.

6. Receptor types Ion-channel Receptors ( Ionotropic Receptors) G-Protein Coupled Receptors (Metabotropic receptors) Kinase-linked Receptors Nuclear receptors

7. LIGAND GATED ION CHANNELS Ionotropic Receptors Typically receptors on which neurotransmitters act Timescale : Milliseconds Localization : Membrane Effector : Ion Channel Coupling : Direct Examples : Nicotinic Ach Receptor, GABAA Receptor, Glutamate Receptor, Glycine receptor, 5 Hydroxytryptamine type 3 (5 – HT3)

8. Nicotinic Ach receptor Pentameric Assembly of 4 types of subunits α, β, y and 8 4 membrane spanning a-helices inserted into membrane 2 Ach binding sites, both must bind Ach molecules for receptor activation Lining of central transmembrane pore formed by helical segments of each subunit (negatively charged AA ). 5 helices sharply kinked inwards halfway, forming a constriction

9. Ach binds to the binding site Twists the alpha subunit and straighten helices, openning of channel Influx of Na + and k + ions Causing depolarization and generation of action potential

10. VOLTAGE OPERATED CHANNELS   These channels open when the cell membrane is depolarised . They underlie the mechanism of membrane excitability Activation induced by membrane depolarisation is short lasting, even if the depolarisation is maintained The most important channels in this group are selective sodium, potassium or calcium channels

11. G-Protein coupled receptors GPCRs are composed of 7 transmembrane helices which have an extracellular domain as drug or neurotransmitter binding site and an intracellular domain that couples to G-protein Metabotropic or 7 – Transmembrane Heptahelical receptors Largest family Timescale : Seconds Location : Membrane Effector : Channel or Enzyme Coupling : G- Protein Examples : adrenoceptors , Muscarinic Ach, histamine, serotonin, opioid, cannabinoid, amine, peptide, prostanoid receptors )

12.  Single polypeptide chain 1100 residues. 7 Transmembrane α-helices, an extracellular N-terminal domain and intracellular C-terminal domain cytoplasmic loop couples to the G- Protein Function of G-Protein: 3 subunits (α, β, γ) are anchored to the membrane through attached lipid residues Coupling of the α subunit to an agonist-occupied receptor causes bound GDP to exchange with intracellular GTP; α–GTP complex dissociates from receptor and from βγ complex Amplification -   A single agonist–receptor complex can activate several G- protein molecules, each of these can remain associated with the effector enzyme for long enough to produce many molecules of product (Second messenger) • Four main classes of G-protein ( Gs , Gi , Go and Gq ) show selectivity with respect to both the receptors and the effectors with which they couple

13. Targets for G proteins Adenylyl cyclase – responsible for cAMP formation Phospholipase C – enyzme responsible for inositol phosphate and diacylglycerol (DAG) formation Ion channels – calcium and potassium channels Rho A/Rho kinase – system the controls the activity of many signaling pathways controlling cell growth and proliferation

14. Ion channel GPCR can control ion channels directly with no secondary messengers Examples : calcium and potassium channels

15. KINASE LINKED AND RELATED RECEPTORS Large , heterogenous group responding mainly to protein mediators. Timescale : Hours Location : Membrane Effector : Protein Kinases Coupling : Direct Examples : Insulin, Growth Factors, Cytokine, ANF receptors Large proteins - single chain ~ 1000 residues, single membrane spanning helical region, with a large extracellular ligand-binding domain, and an intracellular domain of variable size and function. TYPES Receptor tyrosine kinases (RTKs) Serine/threonine kinases Cytokine receptors-lack intrinsic enzyme activity. When occupied, they associate with and activate, a cytosolic tyrosine kinase, such as Jak (the Janus kinase)

16.   SIGNAL TRANSDUCTION Generally involves   dimerization auto phosphorylation of tyrosine residues, act as acceptors for the SH2 domains of intracellular proteins Involved mainly in events controlling cell growth and differentiation, and act indirectly by regulating gene transcription Two important pathways are: the Ras / Raf / MAP kinase pathway - cell division, growth and differentiation . the Jak /Stat pathway activated by many cytokines - controls the synthesis and release of many inflammatory mediators

17. NUCLEAR RECEPTORS Regulate gene transcription. Timescale : Hours Location : Intracellular Effector : Gene transcription Coupling : Via DNA Examples : Steroid Hormones, Thyroid Hormones, Retinoic acid and Vitamin D receptors  

18. MOLECULAR STRUCTURE The N-terminal domain  harbours the AF1 site that binds to other cell specific transcription factors and modifies the binding or activity of the receptor itself . DBD- This Core domain consists of the structure responsible for DNA recognition and binding. They bind to the hormone response elements located in genes to regulate them. Hinge region in the molecule allows it to dimerise with other NRs and also to exhibit DNA binding C-terminal domain contains the ligand binding module and is specific to each class of receptor