PD Principles PDF

“ORPHAN” RECEPTOR - so-called because their ligands are presently unknown, which may prove to be useful targets for the development of new drugs REGULATORY PROTEINS - the best-characterized receptors; modify the actions of endogenous chemical signals (neurotransmitters, autacoids, h...

“ORPHAN” RECEPTOR - so-called because their ligands are presently unknown, which may prove to be useful targets for the development of new drugs REGULATORY PROTEINS - the best-characterized receptors; modify the actions of endogenous chemical signals (neurotransmitters, autacoids, hormones) Other proteins identified as DRUG RECEPTORS Enzymes - may be inhibited (or less commonly activated) by  THEIR TRANSDUCTION COMPONENTS AND MECHANISMS Type I receptors Also known as channel-linked, and ionotropic receptors Activation generates action potentials EPSP (excitatory post synaptic potentials) – are initiated when excitatory neurotransmitter activates Na+ or Ca+2 channels IPSP (inhibitory post synaptic potentials) – are initiated when an inhibitory neurotransmitter open Cl– and K+ channels and membrane becomes hyperpolarized The natural ligands of such receptors include acetylcholine, serotonin, GABA, and glutamate. Examples are nicotinic, 5-HT, GABA and NMDA receptors Type I receptors Ligand gated or receptor operated ion channel (ROC) – activated when a drug or an endogenous substance (neurotransmitter) binds with a specific receptor thus increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane Voltage gated ion channel (VOC) – when a drug or an endogenous substance (neurotransmitter) do not bind directly but are activated by membrane potential Type II receptors Also known as G-protein coupled, “seven- transmembrane” or “serpentine”, and metabotropic receptors The activated effectors produce second messengers that further activate other effectors in the cell, causing a signal cascade effect. Examples are muscarinic, alpha, beta, dopaminergic, glucagon receptors, thyrotropin receptors. Types of G-protein and Second Messenger Systems Gi inhibit Gs Gq adenylyl activate activate cyclase adenylyl Phospholip cyclase ase C Second Messenger Systems Are systems that allow signals from cell surface receptors to be converted and amplified into a cellular response. I. cAMP – produced by adenylyl cyclase II. cGMP – produced by guanylyl cyclase III.IP3, DAG – produced by phospholipase C  Second Messenger Systems Biological actions of cAMP It exertsmost of its effectsby stimulating cAMP- dependent protein kinase A: Mobilization of stored energy Conservation of water by the kidney Calcium homeostasis Increased rate and contractile force of heart muscle Regulate the production of adrenal and sex steroids Relaxation of smooth muscle, and many other endocrine and neural processes  Second Messenger Systems Biological actions of IP3 To facilitate the entry of Ca2 into different cellular compartments + Smooth muscle contraction Increased rate of contraction and relaxation of cardiac myocytes Secretion of transmitter molecules or glandular secretions Hormone release Cytotoxicity Activation of certain enzymes Second Messenger Systems Biological actions of DAG Influences the activity of membrane-bound protein kinase C Modulation of the release of endocrine hormones and neurotransmitters Smooth muscle contraction Inflammation Ion transport Tumor promotion Second Messenger Systems Biological actions of cGMP It has established signaling roles in only a few cell types. It acts by stimulating a cGMP-dependent protein kinase. Relaxation of vascular smooth muscle by a kinase- mediated mechanism that results in dephosphorylation of myosin light chains Type III receptors Also known as enzyme-linked receptors This response lasts on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) possess tyrosine kinase activity as part of their structure. Type IV receptors Also known as nuclearor intracellular receptors. The ligand must diffuse into the cell to interact with the receptor. The primary targets of these ligand– receptor complexes are transcription factors in the cell nucleus. The time course of activation and response of these receptors is on the order of hours to days. Example is hormonal receptors (estrogen receptors)