Biosingaling Tema 10 A (2) PDF

BIOSIGNALING Introduction. Extracellular chemical signals: hormones, neurotransmitters and growth factors. Properties of signal transduction mechanisms Main signal transduction systems: membrane and intracellular receptors Molecular mechanisms...

BIOSIGNALING Introduction. Extracellular chemical signals: hormones, neurotransmitters and growth factors. Properties of signal transduction mechanisms Main signal transduction systems: membrane and intracellular receptors Molecular mechanisms of signal transduction. 1  Introduction Cells have the capacity to receive signals (information through membrane proteins) as a consequence of changes that occur both intracellularly and in the environment. The response (or the action of the cell upon receiving the signal) of the cell to the signals it receives is a way of coping with or responding to the changes produced at the intra- and extracellular level. This property of the cell is essential for its survival. For example: bacteria receive information through membrane proteins about the presence of nutrients, unfavorable conditions in the environment (changes in pH, temperature, presence of toxic compounds, etc.), which translate into responses: movement towards the nutrient, spore formation, etc. In higher organisms, cells with different functions exchange signals to coordinate, for example, metabolic activities between different tissues. The signal received by the cell represents information that is detected by specific receptors and converted into a cellular response, resulting in chemical reactions. This process of converting information into chemical change is called signal transduction. It is a universal property of cells. ❖ Signaling Signaling can be divided into, message reception, message transduction (each molecule in the transduction chain makes a change into the next molecule), and cell response. ❖ Signals Hormones, neurotransmitters and other primary messengers ✓ Cells receive signals from the environment beyond the plasma membrane ✓ These signals cause change in the cell’s composition and function 2  Introduction ❖ Signaling and target cells 3  Characteristics of signal transduction processes a) Specificity: Signal molecules fits c) Desensitization/Adaptation: binding site on its complementary Receptor activation triggers a feedback receptor; other signals do not fit circuit that shuts off the receptor or removes it from the cell surface b) Amplification: When enzymes activate d) Integration: When two signals have enzymes, the number of affected molecules opposite effects on a metabolic characteristic increases geometrically in an enzyme such as the concentration of a second cascade messenger X, or the membrane potential Vm, the regulatory outcome results from the integrated input from both receptors 4  ❖ RECEPTORS G protein-coupled receptors ✓ Example: Epinephrine (adrenaline) receptor. Receptor: A membrane-bound or soluble Enzyme-linked receptors protein or protein complex, which exerts ✓ Example: Insulin receptor a physiological effect (intrinsic effect) Ligand-activated ion channels ✓ Example: Acetylcholine Receptor after binding its natural ligand. Other membrane receptors ✓ Receptors bind specific ligands ✓ Example: Adhesion (integrin) receptors Intracellular receptors ✓ Steroid receptors ❖ LIGANDS Small ions ✓ ferric ion: bacterial ferric receptor Organic molecules ✓ Adrenalin: epinephrine receptor Polysaccharides Ligands: Typical ligands are: ✓ Heparin: fibroblast growth factor Peptides ✓ Insulin: insulin receptor Proteins ✓ Vascular endothelial growth factor 5  ❖ LIGANDS Hormones Substances produced by specialized cells and released to act on other cells (target cells) and modifying their activity. They integrate and coordinate the metabolic activities of the different tissues. a) Classification according to the distance at which they act a) Endocrine: Released into the blood, they act on distant targets. b) Paracrine: released into the extracellular space and act on nearby targets. c) Autocrine: act on the same cell that releases them. b) Classification according to structure 6  Main signal transduction systems: membrane and intracellular receptors. ❖ Signaling through the membrane 7 I/ G-Protein Coupled Signaling (d) Five GPCR structures superimposed to show the remarkable conservation of structure. Shown are the human A2A adenosine receptor (orange; PDB ID 3EML); turkey β1-adrenergic receptor (blue; PDB ID 2VT4), human β2-adrenergic receptor (green; PDB ID 2RH1), rhodopsin from squid (yellow; PDB ID 2Z73); and bovine rhodopsin, (red; PDB ID 1U19). 8  I/ G-Protein Coupled Signaling ▪ G-Protein Coupled Receptors ✓Receptor (GPCRs) are -helical integral membrane proteins ▪ G-proteins are heterotrimeric () membrane-associated proteins that bind GTP ▪ G-proteins mediate signal transduction from GPCRs to ✓G-Protein other target proteins 9  I/ G-Protein Coupled Signaling The three essential components of this signal transduction system are: a) A membrane receptor with 7 α-helices (also called serpentine receptors), b) A G-protein consisting of three subunits (binding guanosine nucleotides) and oscillating between two forms: one activated (with bound GTP) and the other inactive (with bound GDP). C) The third component is the "target" protein, which can be an enzyme or an ion channel, bound to the plasma membrane. The binding of an extracellular signal molecule to a GPCR changes the conformation of the receptor, which allows the receptor to bind to and change the conformation of a trimeric G protein, causing it to open its α- subunit. This makes possible the substitution of GDP for GTP, resulting in cleavage of the α-subunit of the receptor and the βγ-dimer. The α-subunit with GTP and the βγ dimer regulate the activity of other signaling molecules and the receptor remains active as long as the extracellular signal is bound. 10  I/ G-Protein Coupled Signaling I/ 1. Epinephrine Receptor: β-adrenergic receptor Hormone made in adrenal glands (pair of organs on top of kidneys) Mediates stress response: mobilization of energy ✓Binding to receptors in muscle or liver cells induces breakdown of I.1. a. Epinephrine glycogen ✓Binding to receptors in adipose cells induces lipid hydrolysis ✓Binding to receptors in heart cells increases heart rate It serves also as a neurotransmitter in adrenergic neurons. I.1.b. Epinephrine and analogs Isoproterenol and propranolol are synthetic analogs, one an AGONIST with an affinity for the receptor that is higher than that of epinephrine, and the other an ANTAGONIST with extremely high affinity. 11  Sensing the Epinephrine Signal via a G-Protein Coupled Receptor The same adenylyl cyclase molecule in the plasma membrane may be regulated by a stimulatory G protein (GS), as shown, or an inhibitory G protein (Gi, not shown). GS and Gi are under the influence of different hormones. Hormones that induce GTP binding to Gi cause inhibition of adenylyl cyclase, resulting in lower cellular [cAMP]. 12  Synthesis of cAMP cAMP is a secondary messenger ✓ Activates Allosterically cAMP-dependent protein kinase A (PKA) ✓ PKA activation leads to activation of enzymes that produce glucose from glycogen 13  cAMP activate PKA PKA Cyclic AMP-dependent protein kinase A (PKA) without bound cAMP is inactive: the enzyme is in tetrameric form, in which the R regulatory subunits are bound to the catalytic subunits (R2C2).When [cAMP] increases, it binds to the regulatory subunits, dissociating the R2C2 complex, resulting in active C subunits that can phosphorylate many enzymes (depending on the cell type). 14  Signal Amplification in Epinephrine Cascade ✓ Activation of few GPCRs leads to the activation of few adenylyl cyclase enzymes ✓ Every active adenylyl cyclase enzyme makes several cAMP molecules, thus activating several PKA enzymes ✓ These activate thousands of glycogen- degrading enzymes in the liver tissue ✓ At the end, tens of thousands of glucose molecules are released to the bloodstream 15  Self-Inactivation in G-protein Signaling ✓ Epinephrine is meant to be a short-acting signal ✓ The organism must stop glucose synthesis if there is no longer need to fight or flee. 1/ 2/ 16  Self-Inactivation in G-protein Signaling 3/ Removing the -Adrenergic Receptors- epinephrine complex from the membrane 4/ ✓ This process is mediated by two proteins: β- adrenergic protein kinase (βARK) and β- arrestin (βarr; also known as arrestin 2). 17 18 19