KIN 292 1st Edition Lecture 12 Outline of Last Lecture I. Exam 1Outline of Current Lecture I. 5.1 Mechanisms of Intercellular CommunicationII. 5.2 Chemical MessengersIII. 5.3 Signal Transduction Mechanisms Current LectureChapter 5 Chemical Messengers 5.3 Signal Transduction•Messenger binds to receptor•One target may have many types of receptors•Binding results in a cell response•Signal transduction• Process of producing a response in the target after messenger binds to receptorMagnitude of Target Response•Strength of response depends on three factors:•Concentration of the messenger (ligand)•Number of receptors per target cell•The number of receptors per cell varies and is dynamic•Receptor affinity for the messengerEffects of concentration of messenger, target cell receptor concentration and affinity on messenger-receptor binding.Receptor numbers on a cell can change usually for homeostasis purpose↑# is upregulation, results in ↑sensitivity to MEx. GLUT4 by insulin or chronic low [M]↓#s is downregulation, results in ↓ sensitivity to MThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.Ex. Development of tolerance to a drugMessenger-receptor binding is brief and reversibleAgonists and Antagonists – usually drugs•Agonist. Example – histamine (see DISCOVERY p. 127)•Chemical that binds to a receptor•Its action mimics the normal response•Antagonist. Examples – Antihistamines such as Benadryl•Chemical that binds to a receptor•Binding does not result in a response•Competes with the normal ligand•Response is the opposite of that to an agonistMechanisms: Signal Transduction•Intracellular-mediated responses•Membrane-bound receptor-mediated responses•Channel-linked receptors•Enzyme-linked receptors•G protein–linked receptorsMechanisms: Signal Transduction1. Intracellular-Mediated Response•Characteristic of lipophilic ligands•Receptors are found in the cytosol or nucleus•Cell response is via gene activation•General mechanism - next slide( from picture) HRE – portion of DNA regulated by hormones. Next slide (Fig 5.12) fordetails of dimerization of steroid and thyroid hormones leading to bindingHormone Response ElementMechanisms: Signal Transduction2. Membrane-bound receptor-mediated responses•Response of the target takes one of two forms:•Movement of ions•Phosphorylation of enzymes•Overview of mechanisms•Channel-linked receptors (Fast ligand-gated channels)•Enzyme-linked receptors•G protein–coupled receptors (GPCRs)Channel-Linked Receptors•Fast ligand-gated channels•Receptor and channel—same protein•Action is direct•Binding of ligand causes the channel to open or close•Change in transport of ions through the channel causes the target response•Examples on next 2 slidesFigure 5.13 Fast ligand-gated channels and the mechanism by which they change the electricalproperties of cells.Figure 5.14 Fast ligand-gated calcium channels.Enzyme-Linked Receptors•Receptor and enzyme—same protein•Ligand binding activates the enzyme•Action is direct•Activated enzyme causes the target response•Examples: Tyrosine kinases and guanylate cyclases•Receptor Tyrosine Kinases http://www.youtube.com/watch?v=ObrsQlvPA4•https://www.youtube.com/watch?v=Ia6OjvBazGEFigure 5.15 An enzyme-linked receptor.G Protein–Coupled Receptors•G proteins are regulatory proteins•G proteins link ECF messenger to•Ion channels•Amplifier enzymes•ECF messenger = first messenger•The receptor, not the ECF messenger, binds to guanosine (the G in "Gprotein") nucleotidesG proteins and second messengers•cAMP 2nd messenger system•http://www.youtube.com/watch?v=-gUC7ZQTp34•Phosphatidylinositol 2nd messenger system•http://www.youtube.com/watch?v=2bbBrpgeheYSignal Amplification•Small amounts of ligand can cause a huge response in the target•Each step recruits more participants•Characteristic of second messengers• Small amounts of ligand can cause a huge response in the target• Each step recruits more participants• Characteristic of second messengersOther important 2nd messenger systems that work by signal amplificationRemaining slides show additional figures and text to complement theFigure 5.17 The cAMP second messenger system.Figure 5.18 The phosphatidylinositol second messenger system.Figure 5.16 G proteins may also open ion channels. Action of a G proteinon a slow ligand-gated ion channel.G Protein–Coupled Receptors•Slow ligand-gated channels•Receptor and channel—different proteins•Receptor and channel are linked by the G protein•Binding of the ligand activates the G protein, which activates the channel•Action is indirect•Change in transport of ions through the channel causes the target responseG Protein–Linked Receptors•Second messengers•Intracellular messengers•Triggered by the first messenger (ligand) activating the G protein–coupled receptor•The receptor activates the G protein•The G protein activates the amplifier enzyme•The amplifier enzyme activates second messenger