Intercellular Communication PDF

Intercellular Communication BY Dr. Bassam Mohamed Ali Lecturer of Biochemistry Faculty of Pharmacy October 6 University  Cell signaling is a part of a complex system of communication that controls basic cellular activities and coordinates cell actions. Cell signaling is abo...

Intercellular Communication BY Dr. Bassam Mohamed Ali Lecturer of Biochemistry Faculty of Pharmacy October 6 University  Cell signaling is a part of a complex system of communication that controls basic cellular activities and coordinates cell actions. Cell signaling is about communication between different group of cells and tissues… how one group of cells inform another group of cells what to do. The ability of cells to perceive and correctly respond to their environment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancer and diabetes. By understanding cell signaling, diseases may be treated effectively. Why do cells communicate? ✓ During development, cells differentiate to adopt specialized roles ✓ Cells need to know whether to live, die, or divide ✓ Neurotransmission ✓ Contraction-relaxation ✓ Sexual functions and characteristics ❑ Cells may require multiple signals to survive, additional signals to grow and divide and other signals to differentiate. ❑ If deprived of signals, most cells undergo a form of cell suicide.  Overview of Cell Signaling Signals = Stimuli = Ligands: are molecules that released by signaling cells. Steps in Cell Signaling: SYNTHESIS OF SIGNALING MOLECULES RELEASE OF SIGNALING MOLECULES TRANSPORT OF SIGNAL TO TARGET CELLS DETECTION & BINDING OF SIGNAL BY SPECIFIC RECEPTOR CHANGES DUE TO RECEPTOR-SIGNAL COMPLEX SIGNAL REMOVAL & RESPNOSE TERMINATION Classification of Intercellular Communication: Intercellular signaling is subdivided into the following classifications: ❑ Autocrine signals → target the cell itself. Example: immune cells. ❑ Paracrine signals → target cells in the vicinity of the emitting cell. Example: neurotransmitters. ❑ Endocrine signals → target distant cells. Endocrine cells produce hormones that travel through blood to reach all parts of the body. ❑ Juxtacrine signals → target adjacent (touching) cells. → are transmitted along cell membranes via protein or lipid components integral to the membrane. → affect either the emitting cell or immediately adjacent cells. AUTOCRINE SIGNALING PARACRINE SIGNALING ENDOCRINE SIGNALING JUXTACRINE SIGNALING Stages of cell signaling (Phases of Signal Transduction): Reception: o It's the cell's detection of a signaling molecule coming from outside of the cell. o The signal is detected when the molecule binds to the receptor located at the cell's surface or inside the cell. Transduction: o It is a series of steps by which a signal on a cell surface is converted into intracellular signals (i.e. the signal is converted to a form that can bring specific cellular response). o It can occur in a single step or multiple steps needing different relay molecules. Response: o It's the stage of cell signaling where the signal finally triggers a specific cellular response (e.g. movement, growth, division,…etc).  Overview of Cell Signaling & Signal Transduction ❑ Interaction between ligand and receptor → generation of second messengers WHAT ARE RECEPTORS ? ▪ Receptors are proteins associated with the cell membrane or located within the cell. ▪ Binding of receptors by signaling molecules → cell behavior ( = cell response). Intracellular Receptors o Found inside the cell (Cytoplasm or nucleus) o Signal molecule must cross plasma membrane (is hydrophobic or very small) Plasma Membrane Receptors o In plasma membrane o Bind to water-soluble ligands Types of Receptors: 1) Ion channel receptors 2) G-protein-coupled receptors 3) Kinase-linked receptors 4) Nuclear receptors 1. Ion channel receptors: Are cell surface receptors found in all cells and are involved in regulating the passage of specific ions into and out of the cell. Ion Channels Types Ligand-Gated Ion Channels Specific signal molecules cause ligand-gated ion channels to open or close. Incoming ions trigger the response. 2. G protein coupled receptors: G-proteins are membrane-bound proteins linked to the cytoplasmic face of the membrane. G-protein is so called because its signaling mechanism utilizes GDP (guanosine diphosphate) and GTP (guanosine triphosphate). G-proteins are composed of 3 subunits (α, β and γ): ▪ Unique structure of their α-subunits. ▪ βγ subunits appear to be similar across families. G-proteins are classified according to: ▪ Structure of α-subunit. ▪ Name of second messenger of G-protein. G-protein coupled receptors (GPCR) are membrane receptors that works with the help of a G-protein. GPCR family includes: ▪ receptors for numerous hormones and neurotransmitters such as epinephrine, glucagon and serotonin. ▪ light activated receptors in the eye (rhodopsins). ▪ odorant receptors in the nose. Activation of the G alpha subunit of a G-protein-coupled receptor In unstimulated cells, the state of G alpha (orange circles) is defined by its interaction with GDP, G beta-gamma (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Upon receptor stimulation by a ligand called an agonist, the state of the receptor changes. G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell.  G protein-linked reception: A G protein alpha subunit binds either GTP or GDP depending on whether the protein is active (GTP) or inactive (GDP). In the absence of a signal, GDP attaches to the alpha subunit, and the entire G protein-GDP complex binds to a nearby GPCR. When a signaling molecule joins with the GPCR, a change in the conformation of the GPCR activates the G protein, and GTP physically replaces the GDP bound to the alpha subunit. The G protein subunits dissociate into two parts: the GTP-bound alpha subunit and a beta-gamma dimer. Both parts remain anchored to the plasma membrane, but they are no longer bound to the GPCR, so they can now diffuse laterally to interact with other membrane proteins. G proteins remain active as long as their alpha subunits are joined with GTP. However, when this GTP is hydrolyzed back to GDP, the subunits once again assume the form of an inactive heterotrimer, and the entire G protein reassociates with the now-inactive GPCR.  G proteins work like a switch — turned on or off by signal- receptor interactions on the cell's surface. Whenever a G protein is active, both its GTP-bound alpha subunit and its beta-gamma dimer can relay messages in the cell by interacting with other membrane proteins involved in signal transduction. Specific targets for activated G proteins include: ▪ Various enzymes that produce second messengers. ▪ Certain ion channels that allow ions to act as second messengers. Some G proteins stimulate the activity of these targets, whereas others are inhibitory.  One especially common target of activated G proteins is adenylyl cyclase, a membrane-associated enzyme that, when activated by the GTP-bound alpha subunit, catalyzes synthesis of the second messenger cyclic AMP [cAMP] from molecules of ATP. In humans, cAMP is involved in responses to sensory input, hormones, and nerve transmission, among others. 3. Kinase-linked receptors: These receptors consist of: external domain, which functions as ligand binding site, transmembrane domain and cytoplasmic domain.  These receptors have tyrosine kinase in their structure that can transfer phosphate group from ATP to another protein in a cell, which alters cell behavior. Kinase-linked receptors regulate the growth, proliferation, differentiation and survival of cells. Mutations in kinase have been shown to activate the kinase domain, and the protein loses its capacity to be inactivated → uncontrolled growth of the cell (cancer). Receptor Tyrosine Kinases Tyrosine Kinase: Membrane proteins that form dimers. Kinase: Enzyme that phosphorylates. Dimer: Molecule formed by 2 subunits. Phosphatase: Enzyme that dephosphorylates. ❑ Step 1: Ligands bind to receptors, and they form a dimer (Each tyrosine kinase adds a phosphate from an ATP molecule to activate) ❑ Step 2: Receptor protein is activated and starts cellular responses for each phosphorylated tyrosine. Receptor Tyrosine kinases can activate multiple cellular responses (G-proteins can only do one). 4. Nuclear receptors: ❑ Nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. ❑ A unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. ❑ Nuclear receptors are classified as transcription factors because they have the ability to directly bind to DNA and regulate the expression of adjacent genes. ❑ Nuclear receptors work with other proteins to regulate expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism. ❑ Ligands are sufficient lipophilic to cross the cell membrane and bind to nuclear receptor. ❑ Nuclear receptors are maintained inactive. When the ligand binds to it, the ligand-receptor complex is then transported to the nucleus, where it binds to specific DNA sequence and regulates transcription. ❑ Ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up- or down-regulation of gene expression.