Hormones & Cell Signaling 2023 PDF

Popławski Tomasz HORMONES & CELL SIGNALING  from the Greek word “hermon” – to excite or set into motion  chemicals produced in 1 area of the body that have an effect in another area  Named according to the affect they have on the body, not based on the location they are made...

Popławski Tomasz HORMONES & CELL SIGNALING  from the Greek word “hermon” – to excite or set into motion  chemicals produced in 1 area of the body that have an effect in another area  Named according to the affect they have on the body, not based on the location they are made 2 (a) the anatomical description of cells A and B and their immediate environment, as well as the distance between A and B; (b) the chemical structure of the hormone(H); (c) the details of the biosynthesis of the hormone by cell A; (d) the mode of transfer of H from cell A to cell B; (e) the detailed mechanism by which cell B uses receptors to detect the presence of H; (f) how cell B transduces the presence of H to initiate and sustain a biological response; (g) how cell B communicates via a feedback loop with cell A to indicate the adequate presence of the hormone 3 4 5 6 7  Autocrine: ligands function internally and on other target cells.  Paracrine: ligands target cells only in the vicinity of the original emitting cell.  Endocrine: hormones that target distant cells and often travel through our circulatory system.  Intracrine: ligands are produced by the target cell; they bind to a receptor within the cell.  Juxtacrine: ligands target adjacent cells. 8 9  Each cell type displays a set of receptors that enables it to respond to a set of signal molecules  An individual cell often requires multiple signals  to survive (blue arrows)  to grow and divide (red arrows)  to differentiate (green arrows).  If deprived of appropriate survival signals, a cell will undergo a form of cell suicide known as apoptosis. 10 A - The chemical structure of acetylcholine. B–D - Different cell types are specialized to respond to acetylcholine in different ways. 11  Three classes of cell-surface receptors. 12 A - Ion-channel-coupled receptors, B - G-protein-coupled receptors, C - enzyme-coupled receptors.  The signal molecule usually binds to a receptor protein that is embedded in the plasma membrane of the target cell.  The receptor activates one or more intracellular signaling pathways, involving a series of signaling proteins.  One or more of the intracellular signaling proteins alters the activity of effector proteins and thereby the behavior of the cell. 13  Two types of intracellular signaling proteins (A) A protein kinase covalently adds a phosphate from ATP to the signaling protein, and a protein phosphatase removes the phosphate. (B) A GTP- binding protein is induced to exchange its bound GDP for GTP, which activates the protein 14  GAPs inactivate the protein by stimulating it to hydrolyze its bound GTP to GDP, which remains tightly bound to the inactivated GTPase.  GEFs activate the inactive protein by stimulating it to release its GDP 15  (A) a transcription regulator is kept in an inactive state by a bound inhibitor protein. In response to some upstream signal, a protein kinase is activated and phosphorylates the inhibitor, causing its dissociation from the transcription regulator and thereby activating gene expression.  (B) a sequence of four steps, including two sequential inhibitory steps that are equivalent to a single activating step 16 A receptor and some of the intracellular signaling proteins it activates in sequence are preassembled into a signaling complex on the inactive receptor by a large scaffold protein 17 A signaling complex assembles transiently on a receptor only after the binding of an extracellular signal molecule has activated the receptor; here, the activated receptor phosphorylates itself at multiple sites, which then act as docking sites for intracellular signaling proteins 18 Activation of a receptor leads to the increased phosphorylation of specific phospholipids (phosphoinositides) in the adjacent plasma membrane; these then serve as docking sites for specific intracellular signaling proteins, which can now interact with each other. 19  Types of interaction domains in signaling proteins.  Src homology 2 (SH2) domains,  phosphotyrosine-binding (PTB) domains,  Src homology 3 (SH3) domains,  pleckstrin homology (PH) domains. 20 21 Response timing varies in different signaling systems, according to the speed required for the response. Synaptic signaling, the response can occur within milliseconds. The control of cell fate by morphogens during development, a full response can require hours or days 22 Sensitivity to extracellular signals vary greatly. Hormones tend to act at very low concentrations on their distant target cells, which are therefore highly sensitive to low concentrations of signal. Neurotransmitters, operate at much higher concentrations at a synapse, reducing the need for high sensitivity in postsynaptic receptors. Sensitivity is controlled by changes in the number or affinity of the receptors on the target cell. A mechanism for increasing the sensitivity of a signaling system is signal amplification 23  Dynamic range of a signaling system is related to its sensitivity.  responsive over a narrow range of extracellular signal concentrations.  responsive over a much broader range of signal strengths. 24  Persistence of a response vary greatly!  A transient response  A prolonged or even permanent response  Numerous mechanisms can be used to alter the duration and reversibility of a response. 25  Signal processing can convert a simple signal into a complex response.  A gradual increase in an extracellular signal is converted into an abrupt, switchlike response.  A simple input signal is converted into an oscillatory response, produced by a repeating series of transient intracellular signals.  Feedback lies at the heart of biochemical switches and oscillators 26  Integration allows a response to be governed by multiple inputs. 27  Coordination of multiple responses in one cell can be achieved by a single extracellular signal.  Coordination depends on mechanisms for distributing a signal to multiple effectors  branches in the signaling pathway! 28 29  A stimulus activates protein A, which, in turn, activates protein B. Protein B then acts back to either increase or decrease the activity of A 30 31 The mechanisms shown here that operate at the level of the receptor often involve phosphorylation or ubiquitylation of the receptor proteins 32 Alternative splicing of mRNA for hormones 33 Many protein and peptide hormones (right) are synthesized within a larger precursor protein (left). The process is catalyzed by specific proteases that cleave the protein at specific sites (vertical lines), usually preceded by two basic amino acids. This processing takes place in the endoplasmic reticulum and Golgi apparatus prior to the secretion of the hormones. The top example - many hormones are synthesized with one or two N-terminal portions which are sequentially removed to form the active hormone. The second example - several different active peptides are within a single precursor protein, which is processed differently in different cell types, Thirdly, a precursor protein can contain several copies of the hormone, each of which is excised at a pair of specific proteolytic sites. 34 35 36  a ligand-binding domain that noncovalently but stereospecifically binds the correct hormone for that receptor  an effector domain that responds to the presence of the hormone bound to the ligand domain and initiates the generation of the biological response(s). 37 38 39 40 41 The coordination of a Zn 2+ atom (blue) by four cysteines (pink) causes the formation of a loop. One of these, C1, which contains the P-box (light green), is involved in binding to the specific DNA binding site and discriminating between closely related sites for different hormones. The D-box (dark green) in the second zinc finger, CII, plays a role in receptor dimerization. 42 43 The cleavage by phospholipase C of phosphatidyl inositol 4,5- bisphosphonate into diacylglycerol (DAG) and inositol 1,4,5,- triphosphate (IP 3 ) is shown 44 45 46 47 48 49 50 51 Smell and Vision Depend on GPCRs That Regulate Ion Channels (A) A section of olfactory epithelium in the nose. Olfactory receptor neurons possess modified cilia, which project from the surface of the epithelium and contain the olfactory receptors, as well as the signal transduction machinery. The axon, which extends from the opposite end of the receptor neuron, conveys electrical signals to the brain when an odorant activates the cell to produce an action potential. In rodents, at least, the basal cells act as stem cells, producing new receptor neurons throughout life, to replace the neurons that die. (B) A scanning electron micrograph of the cilia on the surface of an olfactory neuron 52 53 There are about 1000 discs in the outer segment. The disc membranes are not connected to the plasma membrane. The inner and outer segments are specialized parts of a primary cilium. A primary cilium extends from the surface of most vertebrate cells, where it serves as a signaling organelle. 54 55 56 57