AN INTRODUCTION TO

RECEPTORS

RECEPTORS
• DEFINITION • CLASSIFICATION • MOLECULAR STRUCTURE IN BRIEF • SIGNIFICANCE

CONECPT OF RECEPTOR
Pioneers • A.J. CLARK : Receptor theory • J.N LANGLEY : Nicotine, Atropine,Pilocarpine • PAUL EHRLICH : Lock - Key • RAYMOND AHLQUIST : Adrenoceptors

TARGETS FOR DRUG ACTION
PROTEIN TARGETS • RECEPTORS • ION CHANNELS • ENZYMES • CARRIER MOLECULES (TRANSPORTERS). NON-PROTEIN TARGETS-Binding, neutralising, osmosis etc.

RECEPTORS

ION CHANNELS

ENZYMES

CARRIER MOLECULES (TRANSPORTERS).

ACTIONS OF DRUGS NOT MEDIATED BY ANY OF THESE

• Therapeutic neutralization of gastric acid by a base (antacid). • Drugs: Mannitol -increasing the osmolarity of various body fluids and causing changes in the distribution of water to promote diuresis, catharsis, expansion of circulating volume in the vascular compartment, or reduction of cerebral edema • Cholesterol-binding agents,(cholestyramine resin) to decrease dietary cholesterol absorption.

RECEPTORS
• The term receptor: any cellular macromolecule to which a drug binds to initiate its effects. • Molecular structure (?) on the surface of or within the cell to which the ligand bind • A molecule which binds (attaches) to a receptor is called a LIGAND ; - a peptide, or other small molecule, such as a neuorotransmitter, hormone, chemical/ drug or a toxin. • A class of cellular macromolecules (cellular proteins) that are concerned specifically and directly with chemical signaling between and within cells. • Combination of a hormone, neurotransmitter, or intracellular messenger with its receptor(s) results in a change in cellular activity. • A receptor functions: recognize the particular molecules that activate (act as receptors for endogenous regulatory ligands)+ Message propagation (alter cell function)

RECEPTOR • Macromolecules that bind mediator substances and transduce this binding into an effect, i.e., a change in cell function. • The component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug's observed effects. • Isolation and characterization -the molecular basis of drug action.

Transmembrane Receptor

• •

RECEPTORS Ligand binding and message propagation (i.e., signalling) Functional domains within the receptor: a ligand-binding domain and an effector domain. The regulatory actions of a receptor : Directly on its cellular target(s), effect or protein(s), or may be conveyed by intermediary cellular signaling molecules : Transducers. The receptor, its cellular target, and any intermediary molecules : Receptor–effector system or signal-transduction pathway An enzyme or transport protein that creates,moves, or degrades a small metabolite (e.g., a cyclic nucleotide or inositol trisphosphate) or ion (e.g., Ca2+) : Second messenger. (Neuromediator) Eg; cAMP.IP3, DAG, PDE etc Second messengers : diffuse in the proximity of their binding sites and convey information to a variety of targets, which can respond simultaneously to the output of a single receptor binding a single agonist molecule.

• Receptor–transducer–effector–signal termination complexes— established via protein–lipid and protein–protein interactions. • Receptors and their associated effector and transducer proteins also act as integrators of information as they coordinate signals from multiple ligands with each other and with the metabolic activities of the cell. • An important property of physiological receptors : Excellent targets for drugs- they act catalytically and hence are biochemical signal amplifiers. The catalytic nature of receptors is obvious when the receptor itself is an enzyme • A single agonist molecule binds to a receptor that is an ion channel, hundreds of thousands to millions of ions flow through the channel every second. • Similarly, a single steroid hormone molecule binds to its receptor and initiates the transcription of many copies of specific mRNAs, which, in turn, can give rise to multiple copies of a single protein.

D-R Chemical Bonds
DRUG- RECEPTOR COMPLEX • Hydrogen • Covalent • Ionic • Vander Waals Structure Activity Relationship ( SAR) Lock Key Theory

• Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed AGONISTS (Affinity and efficacy: 1) • Agents those bind to receptors without regulatory effect, but their binding, blocks the binding of the endogenous agonist.: ANTAGONISTS (Affinity1, efficacy 0) • Agents that are only partly as effective as agonists no matter the dose employed are: PARTIAL AGONISTS ( Affinity 1, Efficacy <1) • Agents that stabilize the receptor in its inactive conformation are termed INVERSE AGONISTS ( Affinity 0; Efficacy -1 ) • The strength of the reversible interaction between a drug and its receptor, as measured by their dissociation constant, is defined as the affinity of one for the other.

MOLECULAR STRUCTURE OF RECEPTORS : FAMILIES • The molecular organisation : Four receptor families • Individual receptors show considerable sequence variation in particular regions • Lengths of the main intracellular and extracellular domains- vary from one to another within the same family • The overall structural patterns and associated signal transduction pathways are very consistent.

RECEPTOR HETEROGENEITY AND SUBTYPES
• Receptors within a given family : Molecular varieties, or subtypes, with similar architecture; differences in their sequences, pharmacological properties. • Distinct subtypes occur in different regions/organs, and these differ from the receptors in other organ Eg: AchNicotinic • The sequence variation that accounts for receptor diversity arises at the genomic level, i.e. different genes give rise to distinct receptor subtypes.
• A single gene can give rise to more than one receptor isoform.

After translation from genomic DNA, the mRNA contains noncoding regions that are excised splicing before the message is translated into protein.

• Splicing : result in inclusion/deletion of one/more of the mRNA coding regions, giving rise to long or short forms of the protein.
(eg: GPCR)

RECEPTOR HETEROGENEITY AND SUBTYPES

• Molecular heterogeneity : feature of receptors- functional proteins in general. • New receptor subtypes and isoforms : options for therapy • Pharmacological viewpoint: To understand individual drugs action, effects; Molecular pharmacology.

TYPES/FAMILIES OF RECEPTORS

Based on molecular structure and the nature of the linkage (the transduction mechanism)

 Ligand-gated ion channels (Ionotropic) Nicotinic acetylcholine receptor, GABA A receptor  G-protein-coupled receptors (GPCRs)/Metabotropic Muscarinic acetylcholine receptor, adrenoceptors  Kinase( Tyrosine)-linked and related receptors Insulin, growth factors, cytokine receptors  Nuclear/ Cytosol receptors steroids, thyroid hormones, gonadal steroids,vit D

Ion Channel Linked
• The molecules responsible for transduction are ions (e.g., Na+ or Ca2+) that are normally found outside of cells. • Binding of a ligand to the receptor results in an opening of a gate through the plasma membrane (hyperpolaristaion/depolaristaion) that allows entrance of the ions (both gate and receptor are proteins, likely one in the same protein). • The increased ion concentration in the cytoplasm propagates
– signal transduction – results in a direct stimulation of a response.

• Oligomeric assembly of subunits surrounding central pore • The rectangular segments: hydrophobic α-helical regions of protein,(20a.a)membr ane-spanning domains of the receptors • Comprise four or five subunits of the type • The whole complex contain:16-20 membrane-spanning segments surrounding a central ion channel

Structure of the nicotinic acetylcholine receptor (a typical ligand-gated ion channel) • The five receptor subunits (α2, β, γ, δ) : a cluster surrounding a central transmembrane pore • Contain negatively charged aminoacids , which makes the pore cation selective. • Two acetylcholine binding sites in the extracellular portion of the receptor, at the interface between the α and the adjoining subunits. • On ACh binding: kinked α helices straighten out or swing out of the way, thus opening the channel pore.

Typical ligand-gated ion channel receptor

• •

Ligand-gated Ion Channel Receptor The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two α-subunits results in opening of the ion channel, with entry of Na+ (and exit of some K+), membrane depolarization, and triggering of an action potential The ganglionic N-cholinoceptors apparently consist only of α and β subunits (α2β2). : GABAA subtypeGlutamate and glycine

GPCR

GPCR
• Typically "serpentine," with seven transmembrane spanning domains, the third one of which is coupled to the G-protein effector mechanism. The signaling molecule binds to the G-protein coupled receptor This causes a change in the receptor so it is able to bind to an inactive G protein. This causes a GTP to replace a GDP which activates a G protein. Receptor systems coupled via GTP-binding proteins (Gproteins) to adenylyl cyclase,(converts ATP to a second messenger cAMP,) that promotes protein phosphorylation by activating protein kinase A. The protein kinase A serves to phosphorylate a set of tissuespecific substrate enzymes, thereby affecting their activity.

• •


GPCR

• Amino acid chain that weaves in and out of the membrane in serpentine fashion
• Seven transmembrane α helices, with an extracellular N-terminal domain of varying length, and an intracellular Cterminal domain

• Binding of the mediator molecule or of a structurally related agonist molecule - change in the conformation of the receptor protein, enabling the latter to interact with a G-protein (=guanyl nucleotidebinding protein).

G-PROTEIN-COUPLED RECEPTORS • The seven α-helical membrane-spanning domains probably form a circle around a central pocket that carries the attachment sites for the mediator substance. • Binding of the mediator molecule or of a structurally related agonist molecule induces a change in the conformation of the receptor protein, enabling the latter to interact with a G-protein (= guanyl nucleotide-binding protein). • G-proteins lie at the inner leaf of the plasmalemma and consist of three subunits designated α, β, and γ. • There are various G-proteins that differ mainly with regard to their α-unit. Association with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion channel). • A large number of mediator substances act via G-protein-coupled receptors

Receptors That Function as Transmembrane Enzymes Tyrosine kinase linked receptors
• Cell-surface receptors, Membrane-spanning macromolecules • Bind a large variety of watersoluble ligands, including amines, amino acids, lipids, peptides, and proteins. • The ligand-binding domain is connected to the cytoplasmic domain by a single transmembrane helix. • In receptors with intrinsic enzymatic activity, the cytoplasmic domain contains a conserved protein tyrosine kinase (PTK) core and additional regulatory sequences that are subjected to autophosphorylation and phosphorylation by heterologous protein kinases • Binding of the ligand causes confirmational changes so that the kinase domains become activated, ultimately leading to phosphorylation of tissue-specific substrate proteins. • It initiates a unique cellular response for each phosphorylated tyrosine.

Tyrosine kinase receptor

Insulin and GH receptor
• The insulin receptor protein : a Ligandoperated enzyme , a catalytic receptor. • When insulin binds to the extracellular attachment site, a tyrosine kinase activity is “switched on” at the intracellular portion. • Protein phosphorylation leads to altered cell function via the assembly of other signal proteins.

• Most growth factor receptors incorporate the ligand-binding and enzymatic (kinase) domains in the same molecule • Cytokine receptors lack an intracellular kinase domain but link to cytosolic kinase molecules

Intracellular Cytosol/ Nulcear Receptors

• Binding of hormones or drugs to receptors releases regulatory proteins that permit of the hormone-receptor complex. • Such complexes interact with response elements on nuclear DNA to modify gene expression. • Eg: drugs interacting with glucocorticoid receptors lead to gene expression of proteins that inhibit the production of inflammatory mediators. • Pharmacologic responses elicited via modification of gene expression are usually slower in onset but longer in duration than other drugs.

Nuclear receptor

Protein synthesis-regulating receptors
• Binding of hormone exposes a normally hidden domain of the receptor protein, thereby permitting the latter to bind to a particular nucleotide sequence on a gene and to regulate its transcription. • Transcription is usually initiated or enhanced, rarely blocked.

SPARE RECEPTORS
• The production of a maximal tissue response when only a fraction of the total number of receptors are occupied • Eg: Acetylcholine analogues in isolated tissues, capable of eliciting maximal responses at very low occupancies, often less than 1%. • The mechanism linking the response to receptor occupancy has a substantial reserve capacity. Such system-said to possess spare receptors, or a receptor reserve. • Common with drugs : smooth muscle contraction; less for : RESPONSESsecretion, smooth muscle relaxation or cardiac stimulation: the effect is more nearly proportional to receptor occupancy. • Do not imply any functional subdivision of the receptor pool, • This surplus of receptors over the number actually needed might seem a wasteful biological arrangement. It means, however, that a given number of agonist-receptor complexes, corresponding to a given level of biological response, can be reached with a lower concentration of hormone or neurotransmitter than would be the case if fewer receptors were provided..

REGULATION OF RECEPTORS
Down regulation • When tissues are continuously exposed to an agonist, the number of receptors decreases-lead to a reduction in the number of receptors.( Tachyphylaxis) . Up regulation • Prolonged contact with an antagonist leads to formation of new receptors-Up regulation.

RECEPTORS AND DISEASE
• Molecular pharmacology: revealed a number of disease states directly linked to receptor malfunction. The principal mechanisms: • Autoantibodies directed against receptor proteins
– Eg: Myasthenia gravis , - autoantibodies that inactivate nicotinic acetylcholine receptors. Autoantibodies can also mimic the effects of agonists, as in many cases of thyroid hypersecretion, caused by activation of thyrotropin receptors

• Mutations in genes encoding receptors and proteins involved in signal transduction.
– Mutations of genes hypoparathyroidism, cancers encoding GPCRs:

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