L11 Cell Signaling (1) PDF

Lecture 11 Cell Signaling Required Reading: Morris text: Chapter 9 Section 9.1 Principles of Cell Signaling Section 9.2 Distance Between Cells Objectives: Signaling Receptors G Protein-coupled Receptors Receptor Kinases Textbook reference sections...

Lecture 11 Cell Signaling Required Reading: Morris text: Chapter 9 Section 9.1 Principles of Cell Signaling Section 9.2 Distance Between Cells Objectives: Signaling Receptors G Protein-coupled Receptors Receptor Kinases Textbook reference sections/pages: Morris text – Chapter 9 (pp. 179-194) Section 9.3 Signaling Receptors (pp. 185-188) Section 9.4 G Protein Coupled Receptors (pp. 188-191) Section 9.5 Receptor Kinases (pp. 191-194) BIOL1010 and BIOL1011  Interactive Activity Using your laptop or phone or tablet… Go to: https://b.socrative.com/login/student/ Or search Socrative Student Enter Room Name: BIOLOGYANA and enter your first and last name You may discuss the answers with others in the class before answering BIOL1010 and BIOL1011 Slide 2  How Do Cells Communicate? All cells process information from the environment Communication required for coordination of activities Communication most often via chemical signals that bind to specific receptors – Hormones, neurotransmitters, CO2, H+ Signals can come from outside the organism, or from neighboring cells; short distances or long Examples of molecules that act a signals: Plants: Animals: – Ethylene – Epinephrine BIOL1010 and BIOL1011 3 Receptor Activation and Receptor Types Receptor: protein that receives and interprets information carried by signaling molecule (ligand) Ligand binds to ligand-binding site on receptor 🠦 conformational shape change in the entire receptor Shape change activates receptor Receptors can be found on: – inside the cell = intracellular receptors – cell surface = cell surface receptors BIOL1010 and BIOL1011 4  Intracellular Receptors – Found inside the cell – Receptor + ligand (if steroid) = steroid–receptor complex Either in cytoplasm or nucleus – Use non-polar signaling molecules: Small and pass freely through plasma membrane Can be a steroid Steroids are hydrophobic; pass through plasma membrane Active steroid-receptor complexes act as transcriptional regulators and control gene expression BIOL1010 and BIOL1011 5  Cell Surface Receptors General structure: 1. Ligand-binding site 2. Extracellular domain 3. Transmembrane domain 4. Cytoplasmic domain 1 2 3 4 BIOL1010 and BIOL1011 6  Cell Surface Receptors (2) Use polar signaling molecules – Small polar proteins, cannot cross plasma membrane Types of cell-surface receptors: – There are thousands of different receptor proteins on the surface of any given cell. – Most can be placed into one of three groups, according to the way they are activated. G protein-coupled receptors Receptor kinases Ion channels BIOL1010 and BIOL1011 7  Cell Surface Receptors (3) Cell Surface Receptors Act Like Molecular Switches – Many receptors exist in two alternative states – on or off – Signaling molecule bound to receptor 🠦 receptor activated (i.e. on) – Signaling molecule not bound to receptor 🠦 receptor inactive (i.e. off) BIOL1010 and BIOL1011 8  Signal Transduction, Response and Termination Signal transduction (and sometimes amplification), response and termination are the steps that occur after a signaling molecule binds to receptor – Although the ligands are different, the subsequent steps are similar BIOL1010 and BIOL1011 9  G Protein-Coupled Receptors Transmembrane proteins with this general structure: i. Ligand binding site – extracellular ii. Transmembrane region - 7 alpha helices iii. G-protein binding site – cytoplasmic Types of signal molecules used by G-protein-coupled receptors: Small molecules Many hormones Neurotransmitters G-protein-coupled receptors are responsible for senses of sight, smell, taste BIOL1010 and BIOL1011 Slide 10  G Protein-Coupled Receptors When ligand binds to G protein-coupled receptor, it is activated When active, it binds to a G protein (cytoplasm) G proteins can be bound to either GDP or GTP (guanine nucleotides) G protein + GTP = active G protein + GDP = inactive Ligand binds 🠦 receptor then binds to G protein 🠦 GDP replaced with GTP and G protein activated 🠦 signal transmitted – Active G protein then activates other proteins as part of signaling pathway BIOL1010 and BIOL1011 11  G Protein-Coupled Receptors Some G proteins are composed of three subunits: α (alpha) β (beta) γ (gamma) α (alpha) subunit binds either GDP or GTP α subunit + GDP 🠦 3 subunits bound = inactive Receptor activated 🠦 GDP on α subunit replaced by GTP 🠦 3 subunits separate = active Activated α subunit binds to and activates target protein 🠦 response BIOL1010 and BIOL1011 12  Example of G Protein Activation and Amplification: Adrenaline Signaling in Heart Muscle Target protein = adenylyl cyclase Activated adenylyl cyclase converts ATP to cAMP (second messenger) cAMP = second messenger cAMP binds to Protein kinase A Activated protein kinase A phosphorylates heart proteins As long as adrenaline is bound to the receptor, the heart rate will remain high. Heart rate increases BIOL1010 and BIOL1011 13  Amplification of Adrenaline Signal A little adrenaline goes a long way! 1 Amplification occurs at several places (1, 2, 3) Small amount of signal 🠦 large response 2 Key Point: Cell response depends on cell type and proteins in it 3 G protein-coupled receptors typically activate downstream enzymes or open ion channels Effects are rapid, short-lived, reversible BIOL1010 and BIOL1011 14  Termination of G protein Signal The amount of time a signaling molecule remains bound to its receptor depends on how tightly the receptor holds on to it, its binding affinity for the signaling molecule. Most ligands do not bind permanently to receptors Signal turns off once ligand is unbound (G protein deactivates itself) GTP to GDP Other parts of the pathway must also turn off Enzymes degrade cAMP to AMP BIOL1010 and BIOL1011 15  Termination of G protein Signal (2) Phosphatases remove phosphate group = dephosphorylation When a protein is dephosphorylated by a phosphatase, it typically becomes inactive BIOL1010 and BIOL1011 16  Receptor Kinases A kinase is an enzyme that adds a phosphate group to another molecule 🠦 phosphorylation Phosphate group comes from ATP When a protein is phosphoryl-ated by a kinase, that protein typically becomes active – Shape change or – Provides new site for other proteins to bind Recall: phosphatases have the opposite effect i.e. remove phosphate group = dephosphorylation BIOL1010 and BIOL1011 17 Receptor Kinase Activation/Transduction Extracellular portion - binds signaling molecule Intracellular portion - is the kinase Dimerization activates cytoplasmic kinase domains causing them to phosphorylate each other at multiple sites on their cytoplasmic tails. Phosphorylated areas provide sites for other proteins to bind and become active. BIOL1010 and BIOL1011 18  Receptor Kinases Where is receptor kinase signaling used? Formation and elongation of limb buds that become our arms and legs Wound healing when we cut ourselves, platelet derived growth factor (PDGF) released from platelets in the blood signals to cells at the wound site, triggering cell division to repair the damage In general, receptor kinases initiate long-term responses Activation of proteins involved in changes in gene expression Cell growth, division, differentiation, shape change BIOL1010 and BIOL1011 19  Receptor Kinase Example: The MAP kinase pathway Paper cut – ouch! Platelets release proteins including PDGF MAP kinase pathway: PDGF binds to receptor kinases on cell surface NB: Dimerization; receptor Ras + GDP 🠦 inactive activation Ras + GTP 🠦 active Ras protein activated (in cytoplasm); GTP bound Kinase series triggered; kinase enters nucleus This pathway becomes inactive once the GTP-bound Ras is Transcription regulators for cell division activated converted to GDP. BIOL1010 and BIOL1011 20  Receptor Kinases A receptor kinase, Kit, responsible for the production of pigment in skin, feathers, scales and hair Mutations in the Kit receptor kinase causes patterns of incomplete pigmentation (white patches) BIOL1010 and BIOL1011 21  Ligand-gated Ion Channels These are receptors that alter flow of ions across plasma membrane (channels) Conformational shape change opens channel – Allows flow of ions in and/or out – Channel remains open as long as the signaling molecule remains bound BIOL1010 and BIOL1011 22  Integration of Signaling Pathways Signaling pathways do not operate independently – signaling is very complex! – In one organism - many different signaling molecules each with own receptors Different signaling molecules can bind to a single cell and activate several signaling pathways simultaneously – final response of a cell depends on how the pathways intersect with one another Also, one signal may inhibit signaling pathway triggered by a another signal and weaken the end response “Molecular cross-talk” BIOL1010 and BIOL1011 23