FUNBIO 11 2024 Membrane Signalling PDF

Fundamentals of Human Biology FUNBIO.11 Biological membranes: Cell signaling P r o f Wa r r e n T h o m a s D A T E : 3 rd O c t o b e r 20 2 4 Learning outcomes Define principles of signal transduction Differentiate between intra- and extra-cellular signalling. Classify signal trans...

Fundamentals of Human Biology FUNBIO.11 Biological membranes: Cell signaling P r o f Wa r r e n T h o m a s D A T E : 3 rd O c t o b e r 20 2 4 Learning outcomes Define principles of signal transduction Differentiate between intra- and extra-cellular signalling. Classify signal transduction proteins Describe secondary messengers Explain ion channel-, G-protein and enzyme linked receptors.  How do cells receive and respond to signals from their surroundings? Ligands (signaling molecules) On one hand, cell signaling regulates gene expression and controls the cell fate (proliferation, motility, Receptor differentiation and programmed cell death, or apoptosis). On the other hand, cell signaling allows for the organization of cells into tissues, which, in turn, generate organs. In addition, cell signaling is essential for the maintenance of cells, tissues and organs. Signaling cells Target cells Cells that produce and release the signaling molecules are signaling cells. Cells that receive the signal are target cells Targets cells posses specific receptors that recognize signaling molecules.  External Signals are Converted to Internal Responses Cells sense and respond to the environment Prokaryotes: chemicals Cell signaling are mechanisms by Humans: which cells communicate with one Light - rods & cones of the eye another Sound – hair cells of inner ear Four main processes: Chemicals in food – nose & tongue 1) Signal transmission 2) Reception 3) Signal transduction Cells communicate with each other 4) Response Direct contact Chemical signals Signal transduction: ability of cell to translate receptor-ligand interaction into a change in behavior or gene expression. The chains of molecules that relay intracellular signals are known as intracellular signal transduction pathways. 1. Sending Signals (Signal Transmission) ❑ Communication among cells is referred as intercellular signaling. ❑ Communication cells to the extracellular matrix is referred as extracellular signaling. ❑ Cells communicate with each other through signaling molecules. Signaling molecules could be: proteins, small peptides, amino acids, nucleotides, steroids, retinoids, fatty acid derivatives, nitric oxide, carbon monoxide Figure 6-3 p134  2. Reception Cell signaling are mechanisms by which cells communicate with one another Four main processes: 1) Signal transmission 2) Reception 3) Signal transduction 4) Response The signals a cell responds to depends on its receptors A ligand binds to a specific receptor and triggers a biological response Hydrophilic molecules bind to protein receptors on the surface of target cells Hydrophobic molecules move through the plasma membrane and bind with intracellular receptors 2. Reception: Three types of cell-surface receptors Ion channel-linked receptors (ligand-gated channels) Found in plasma membrane Convert chemical signals into electrical signals Ion channel opens or closes in response to binding of the signaling molecule (ligand) Example: acetylcholine binds to and opens a ligand-gated sodium ion channel G protein-linked receptors Transmembrane proteins with a binding site for a signaling molecule on the outside, and a binding site for a specific G protein that extends into the cytosol Couple signaling molecules to signal transduction pathways inside the cell More than 400 are potential targets for pharmaceutical interventions Enzyme-linked receptors Transmembrane proteins with a binding site for a signaling molecule outside the cell and an enzyme component inside the cell Bind hormones such as insulin and growth factors Tyrosine kinase: an enzyme that catalyzes transfer of phosphate groups (phosphorylation) from ATP to a specific tyrosine that is part of a protein Figure 6-5 p136  3. Signal Transduction Ligands (signaling molecules) Cell signaling are mechanisms by Receptor which cells communicate with one another Four main processes: 1) Signal transmission 2) Reception 3) Signal transduction 4) Response Signaling cells Target cells Signal transduction: ability of cell to translate receptor-ligand interaction into a change in behavior or gene expression. The chains of molecules that relay intracellular signals are known as intracellular signal transduction pathways.  3. Signal Transduction 1. Signals act over different ranges. 2. Signals have different chemical natures. 3. The same signal can induce a different response in different cell. 4. Cells respond to sets of signals. 5. Receptors relay signals via intracellular signaling cascade.  Principles of Signal Transduction 1. Regulatory molecules activate membrane proteins, which then transduce the signal 2. A signaling molecule binds with a cell-surface receptor and activates it by changing shape of receptor tail that extends into cytoplasm 3. Signal is relayed through a chain of protein kinases and secondary messengers, creating a signaling pathway that amplifies the signal (molecules A, B and C) Each component in a signaling pathway can be active (“on”) or inactive (“off ”) Every activated molecule in a signaling pathway must be inactivated in order to transmit a new signal Molecular switches are typically regulated by the addition or removal of phosphate groups Figure 6-2 p133  Signal Transduction Protein kinase cascade is a signaling pathway in which a series of protein kinase molecules are phosphorylated Signaling Receptor molecule 1 Phosphatase: an enzyme that catalyzes the removal of a phosphate group by hydrolysis Help regulate protein kinase cascades 1. When the receptor is activated, each protein 2 Inactive Active kinase activates the next protein kinase (2->3->4) protein protein in the pathway by phosphorylation of one or kinase 1 kinase 1 Active 3 more of its threonine, serine, or tyrosine residues. protein Addition of a phosphate group typically changes kinase 2 Active 4 the shape of the molecule. Inactive protein 5. Activation of the last protein in the chain protein kinase 3 changes some cell process or turns on (or turns kinase 2 Inactive Active 5 off) specific genes. protein protein kinase 3 (P represents phosphate.) Inactive protein Note that the number of protein kinases varies Alters some cell process from pathway to pathway. Figure 6-6 p138 Second Messengers are Intracellular Signaling Agents Second messengers are molecules that relay signals received at receptors on the cell surface — such as the arrival of protein hormones, growth factors, etc. — to target molecules in the cytosol and/or nucleus. But in addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal. Binding of a ligand to a single receptor at the cell surface may end up causing massive changes in the biochemical activities within the cell. There are 3 major classes of second messengers: 1.cyclic nucleotides (e.g., cAMP and cGMP) 2.inositol trisphosphate (IP3) and diacylglycerol (DAG) 3.calcium ions (Ca2+)  Cyclic Nucleotides (e.g., cAMP and cGMP) Cyclic AMP is a second messenger signaling molecule (first messenger) binds to G protein-linked receptor→ activates G protein → activates adenylyl cyclase → catalyzes the formation of cAMP (second messenger) → activates protein kinase → phosphorylates proteins → response in cell Synthesis and inactivation of cyclic AMP  Inositol Trisphosphate (IP3) and Diacylglycerol (DAG) Inositol-1,4,5-trisphosphate (IP3): This soluble molecule diffuses through the cytosol and binds to Example: receptors on the endoplasmic reticulum causing the The calcium rise is needed for NF-AT release of calcium ions (Ca2+) into the cytosol. The (the "nuclear factor of activated T cells") rise in intracellular calcium triggers the response. to turn on the appropriate genes in the nucleus. The remarkable ability Diacylglycerol (DAG): DAG remains in the inner of tacrolimus and cyclosporine to layer of the plasma membrane. It prevent graft rejection is due to their recruits Protein Kinase C (PKC) — a calcium- blocking this pathway. dependent kinase that phosphorylates many other The binding of an antigen to its receptor proteins that bring about the changes in the cell. As on a B cell (the BCR) also generates its name suggests, activation of PKC requires the second messengers DAG and IP3. calcium ions. These are made available by the action of the other second messenger — IP3.  Calcium ions (Ca2+) In response to many different signals, a rise in the concentration of Ca2+ in the cytosol triggers many types of events such as: Muscle contraction Exocytosis, e.g. Secretion of hormones like insulin Adhesion of cells to the extracellular matrix (ECM) Apoptosis A variety of biochemical changes mediated by Protein Kinase C (PKC).  Getting Ca2+ Into (and out of) the Cytosol Voltage-gated channels Open in response to a change in membrane potential, e.g. the depolarization of an action potential Found in excitable cells: Skeletal muscle Smooth muscle (channels blocked by drugs, such as felodipine, used to treat high blood pressure (bp). influx of Ca2+ contracts the smooth muscle of the arteriole wall, raising bp. Felodipine block this). Neurons- when the action potential reaches the presynaptic terminal, the influx of Ca 2+ triggers the release of the neurotransmitter. Taste cells that respond to salt. Allow some 106 ions to flow in each second following the steep concentration gradient. Receptor-operated channels Found in the post-synaptic membrane and open when they bind the neurotransmitter. E.g. NMDA receptors. G-protein-coupled receptors (GPCRs). Not channels but they trigger a release of Ca2+ from the ER as described above. Activated by various hormones and neurotransmitters (as well as bitter substances on taste cells in the tongue). Ca2+ ions are returned to the ECF by active transport using: ATP-driven pump called a Ca2+ ATPase Two Na+/Ca2+ exchangers. These antiport pumps harness the energy of 3 Na+ ions flowing DOWN their concentration gradient to pump one Ca 2+ against its gradient and 4 Na+ ions flowing down to pump 1 Ca2+ and 1 K+ ion up their concentration gradients. Ca2+ ions are returned active transport to the ER (and SR) using another Ca2+ ATPase.  Signal Transducing Receptors There are 4 Classes of Signal Transducing Receptors: 1. Intracellular Receptors (Cytoplasmic & Nuclear Receptors) Activation of these receptors located within a cell results in directly altered gene transcription. 2. GPCRs (G-Protein-Coupled Receptors) Couple to GTP binding proteins (G-proteins) inside the cell to activate them. Active G proteins modulate the activity of various ion channels and enzymes. 3. Ion Channels Allow specific ions to flow into or out of the cell in response to binding of a chemical messenger 4. Enzyme-Linked Receptors (Receptor Kinases) Have intrinsic enzymatic activity or are associated with an intracellular enzyme. Many Activated Intracellular Receptors are Transcription Factors (TFs) TFs regulate gene expression The ligand-receptor complex binds to a specific region of DNA and activates or represses specific genes. Activated genes produce messenger RNA that carries the code for synthesis of a particular protein into the cytoplasm Signal Transducing Receptors: Ion Channel Receptors Ion Channel Linked Receptors allow specific ions to flow into or out of the cell in response to binding of a chemical messenger (more in FUNBIO7) Examples: Muscle Contraction Nerve Cell communication Signal Transducing Receptors: Enzyme Linked Receptors Enzyme-Linked Receptors (Receptor Kinases) where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Therefore, a catalytic receptor is an integral membrane protein possessing both catalytic, and receptor functions. Examples of the enzymatic activity include: Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type. Serine/threonine-specific protein kinase, as in bone morphogenetic protein Guanylate cyclase, as in atrial natriuretic factor receptor Signal Transducing Receptors: G-Protein- Coupled Receptors GPCRs are transmembrane proteins with a binding site for a signaling molecule on the outside, and a binding Adenylyl cyclase site for a specific G protein that extends into the cytosol Receptor activated Regulate many signal transduction pathways When inactive, G protein has one subunit linked to guanosine diphosphate (GDP) When a signaling molecule binds to the receptor, GDP is replaced by guanosine triphosphate (GTP) GTP releases energy; G protein is deactivated Protein kinase A Some examples of their physiological roles : The visual sense: The opsins use a photoisomerization reaction Protein Phosphorylated to translate electromagnetic radiation into cellular signals. protein Rhodopsin, for example, uses the conversion of 11-cis-retinal to Alters some cell process all-trans-retinal for this purpose. The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal Figure 6-8c p140 receptors) Involved in growth and metastasis of some types of tumors.  Reception Binding of epinephrine Signal to G-protein-linked receptor 1 Cascade (1 molecule) Transduction amplification Inactive G protein Active G protein (102 molecules) 102 Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) 104 Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase 105 Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) 106 Response Glycogen 10 22 8 8  Principles of Signal Transduction EXTRACELLULAR SPACE PLASMA MEMBRANE AM PLI FICA 2. TRANSDUCTION TIO CYTOPLASM N3. RESPONSE 1. RECEPTION Relay molecules in a signal transduction pathway Activation of cellular response Signal molecules Secondary Target Primary Receptor Messengers Enzymes Messenger CASCADE EFFECT Signal trunsduction proteins can be classified into 3 groups: receptors, secondary messengers A check up question: The outer part of a G protein-linked receptor binds to a(n) ____, and its inner part binds to a(n) ____. a. G protein; ion channel b. G protein; tyrosine kinase c. ion channel; G protein d. signaling molecule; G protein e. signaling molecule; tyrosine kinase A check up question: Ion channels are found in the plasma membranes of neurons and muscle cells. a. True b. False AR IA L 1 0. 5 PT Reading: Chapter 6, Biology by Solomon AR IAL 9pt Thank you F O R M O R E I N F O R M AT I O N P L E A S E C O N TA N T P r o f Wa r r e n T h o m a s E MA IL: w ath omas@ rcs i-mub. com