Receptor Types PDF

180px-Transmembrane_receptor Receptors 1  Outline Definitions (receptor, ligand, agonist, antagonist, efficacy, potency) Receptor interactions Receptor theories Dose response relationship Classification of receptors types...

180px-Transmembrane_receptor Receptors 1  Outline Definitions (receptor, ligand, agonist, antagonist, efficacy, potency) Receptor interactions Receptor theories Dose response relationship Classification of receptors types 2 Background Receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which a mobile signaling molecule may attach. Ligand is a molecule which binds to a receptor. Ligand may be a peptide or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. When such binding occurs, the receptor undergoes a conformational change, which ordinarily initiates a cellular response. 3 Background Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action. (the brackets stand for concentrations) 4  Binding affinity Binding affinity is a measure of how well a molecule fits a receptor is the. Binding affinity is inversely related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological response (e.g. second messenger cascade or muscle contraction), is only achieved after a significant number of receptors are activated. 5 DRUG RECEPTOR INTERACTIONS Effect of drug attributed to two factors. Affinity: tendency of the drug to bind to receptor and form D-R complex. Efficacy or intrinsic activity: ability of the drug to trigger pharmacological responses after forming D-R complex. 6 Ligands Not every ligand that binds to a receptor activates that receptor. The following classes of ligands exist: Full agonists are able to activate the receptor and result in a maximal biological response. Most natural ligands are full agonists. Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists. Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists. Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity. 7 Constitutive activity A receptor which is capable of producing its biological response in the absence of a bound ligand is said to display "constitutive activity. The constitutive activity of receptors may be blocked by inverse agonist binding. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). 8  Receptor Interactions Lock and key mechanism Agonist Receptor Agonist-Receptor Interaction 9  Receptor Interactions Competitive Inhibition Antagonist Receptor Antagonist-Receptor DENIED! Complex 10 Receptor Interactions Non-competitive Antagonist Inhibition Agonist Receptor DENIED! 11 ‘Inhibited’-Receptor  Receptor Interactions Induced Fit Receptor Perfect Fit! 12 The occupancy theory: The more receptors' sites occupied by ligand, the stronger response The rate theory: The more ligand-receptor interact / unit time, the stronger response The induced-fit theory: Agonist Receptor + Agonist Conformation A Responce No ligand bound Conformation B + Antagonist Antagonist Responce ConformationA or Inactive conformation C The macromolecular pertubation theory: (induced fit + rate theory) 13 The activation -aggregation theory: Always dynamic equilibr. Agonist + Agonist Responce Responce Conformation B (Active) Antagonist Responce + Antagonist Inv. Agonist Responce B Responce A (opposite of responce A) + Inverse agonist 14 Dose-Responce Relationships A + B A-B [A] - equil. towards AB L + R L-R [L] - equil. towards LR ?? L L-R R locked in membrane (do not move freely) L dissolved in extracellular fluid R Reaction on solid - liquid interface Biological responce 15 Efficacy vs. Potency Efficacy: The maximal effect (Emax) an agonist can produce if the dose is taken to very high levels. Potency: The amount of a drug needed to produce a given effect. 16 % biolog. effect % biolog. effect 100 100 50 50 EC50 [Agonist ligand] EC50 log [Agonist ligand] biolog. effect X Y Efficacy (how high activity is possible) Efficacy X = Efficacy Y (both can give 100% responce) Z Efficacy X> Efficacy Z (Z cam only give ca 30% responce) EC50 X and Y Potency (how easily is a given responce reached (ex EC50) EC50 Z Potency X > Potency Y Potency X = Potency Z Potency Z > Potenzy Y 17 log [Agonist ligand] Classification of receptors Depending on their functions and ligands, several types of receptors may be identified: Peripheral membrane proteins. Transmembrane proteins. Intracellular proteins 18  Receptors Peripheral membrane Trans-membrane Intracellular proteins proteins proteins Metabotropic Ionotropic receptors receptors 1. G protein-coupled receptors 1. Extracellular ligands 2. Receptor tyrosine kinases 2. Intracellular ligands 3. Guanylyl cyclase receptor 19  1.Peripheral membrane proteins These receptors are relatively rare compared to the much more common types of receptors that cross the cell membrane. Example: elastin receptor. 20  3. Intracellular proteins They are located inside the cell rather than on its cell membrane. Examples: 1- the class of nuclear receptors located in the cell nucleus These receptors often can enter the cell nucleus and modulate gene expression in response to the activation by the ligand. 2- the IP3 receptor located on the endoplasmic reticulum. The ligands that bind to them are intracellular 2nd messengers like inositol triphosphate (IP3) upon activation by extracellular hydrophilic hormones like angiotensin, epinephrin. 21  File:Nuclear receptor action.png This figure depicts the mechanism of a class I nuclear receptor (NR) which, in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA which is eventually translated into protein 22 which results in a change in cell function.  File:Type ii nuclear receptor action.png This figure depicts the mechanism of a class II nuclear receptor (NR) which, regardless of ligand binding status is located in the nucleus bound to DNA. The nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the retenoid X receptor (RXR). In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein which in turn recruit additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein which results 23 in a change in cell function. 2. Trans-membrane proteins Examples: Many hormone and neurotransmitter receptors. Trans-membrane receptors are embedded in the phospholipid bilayer of cell membranes, that allow the activation of signal transduction pathways in response to the activation by the binding molecule (ligand). Metabotropic receptors are coupled to G proteins and affect the cell indirectly through enzymes which control ion channels. Ionotropic receptors (also known as ligand-gated ion channels) contain a central pore which opens in response to the binding of ligand. 24 Metabotropic vs. Ionotropic receptors In contrast to ionotropic receptors, metabotropic receptors do not form an ion channel pore; rather, they are indirectly linked with ion-channels on the plasma membrane of the cell through signal transduction mechanisms (G proteins, tyrosine kinases, or guanylyl cyclase). Both receptor types are activated by specific neurotransmitters. When an ionotropic receptor is activated, it opens a channel that allows ions such as Na+, K+, or Cl- to flow. When a metabotropic receptor is activated, a series of intracellular events are triggered that result in ion channel opening but must involve a range of 2nd messengers. 25 Metabotropic receptors G protein-coupled receptors Comprise a large protein family of trensmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. cAMP signal pathway Phosphatidylinositol pathway 26  G-Protein coupled receptors G-protein: Guanine nucleotide binding protein Ligand (Agonist) Extracellular fluid Intracellular fluid Target Conform. change Reseptor    G-protein GTP  +P GDP GDP GDP      O  HN N GTP H 2N N N GTP Responce O O O P O P O n=1; GDP O n=2; GTP O O n 27 HO OH  Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C One ligand can bind to more than one type of G-prot. coupled reseptors second messenger pathways NH2 NH2 Adenylyl cyclase N N N N N N Activate c-AMP dependent protein kinases O O O N N O P O P O P O O (Phosphoryl. of proteins, i.e. enzymes) O O O O O P O P O P O OH HO OH O Various responces (ex. metabolism, cell division) ATP c-ATP 28  Subtypes of G-proteins - Targets (Second messenger systems) Ion chanels: G12 Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C Various processes in cell Various processes in cell second messenger pathways Activate protein kinases Release Ca2+ R' O O O R' O O P O Phopholipase C O O OH R O O O + O R HO O O HO O P O P OH O OH O P HO O DAG HO IP3 P Diacylglycerol O Inositol-1,4,5-triphosphate P PIP2 Phosphatidylinositol besphophate Several steps Li (Treatmen manic depression) 29  Gs cAMP Dependent Pathway hormon Inhibit EXTRACELLUL e or A R RS Ri A GTDPP  C  GDP CYTOSOL GTP ATP ATP Inactive Protein protei cAM kinas n P e ADP Active Adenylate cyclase protein Signaling System Cell response30 Gi cAMP Dependent Pathway 31 Gq Protein Coupled Receptor EXTRACELLUL A R CYTOSOL 32 Metabotropic receptors Receptor tyrosine kinases Receptor tyrosine kinases (RTK)s are the high affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones. Receptor tyrosine kinases have been shown to be not only key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Examples: VEGFR, FGFR 33 Enzyme coupled receptors - Catalytic receptors Ligands: Peptide hormones 1) Binding of Ligand 2) Dimerisation of reseptor Phosphoryl of Tyr Tyr kinase -OH -OH -OH domain (Janus kinase) (JAKs) STATS protein O P O P STATS O P O P 1) Phosphoryl. of STAT protein 2) Release of STAT in cytoplasma 3) STATto cell nucleus 4) Intitation of transcription STAT: Signal transducers and activators of transcription 34 Metabotropic receptors Guanylyl cyclase receptor Is another enzyme-linked receptor. Same principle of receptor tyrosine kinases. 35 Ionotropic receptors Ion channel-linked receptors are involved in rapid signaling events most generally found in electrically excitable cells such as neurons and are also called ligand-gated ion channels. Opening and closing of Ion channels are controlled by neurotransmitters. Example: nicotinic receptor of Acetylcholine. 36 Ligand-gated ion channels Ligands Ligand binding sites Fast neurotransmitters ex. Acetylcholine (nicotinic receptors) Membrane (Phospholipides) Ion chanel Fastest intracellular response, ms Binding of ligand - opening of channel - ion (K+, Na+) in or out of cell - response 37  Summary Endogenous ligands General structures Fast neurotransmitters Ligand gated ion channels ex. Acetylcholine Slow neurotransmitters G-Protein coupled receptor ex. noradrenaline Insulin Enzyme coupled receptors Growth factors Catalytic receptors Steroid hormones Cytoplasmic receptors Thyroid hormones Vitamin A, D 38 Receptor subtypes Somatic nervous system Autonomic nervous system Most receptor classes - several sub-types Each subtype - different A(nta)gonists sympathetic parasympathetic Det somatiske nervesystem Det autonome nervesystem Det sympatiske Det parasympatis ke nerves ystem nerves ystem Sub types cholinergic receptors CNS CNS CNS Acetylcholine ganglion Acetylkolin Noradrenalin Synapse Muscarinic Reseptor receptors Nicotinic Effektor celle M1: G-Protein coupled receptors receptors 4.3 Å Stimulate phopholipase A Nmuscle: Ligand gated ion chanels 5.9 Å HO M2: G-Protein coupled receptors Incr. Na+/Ca2+ O N Inhib. adenylyl cyclase N Nneuro: Ligand gated ion chanels O H N H Incr. Na+/Ca2+ H O 39 Any Questions?? 40