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Lecture 9

Lecture 9 Signal transduction.docx

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Biology 2382B
Robert Cumming

Lecture 9 – Basic Principles of Cell Signaling and GPCR System Signal Transduction  Conversion of one singal into another  Some intrinsic factors – external stimuli and how our cells respond to it  Invovles growth factors, cytokines, hormomnes, ECM, neurotransmitters, light sound. Etc.  Initiator of diseases – “Cancer, Heart, Diabetes” Basic Elements of Cell Signalling  Primary Signal or signaling molecule (ligand, primary messenger) o Small molcules (epinephrine, acetylcholine, steroids) , peptide hormons, monoamines etc. o Large molecules, growth factors cytokines (proteins) o This will illicit its initial effect on the receptor  Receptors o Cell-surface receptors – has a component or works outside of the cell o Intraellular receptors – receptors that are found inside of cells o These receptors will transmit a signal: This is done by – o Interacting with other proteins, effector proteins o Receptors after receiving signal will then do something –  Intracellular signaling and effector proteins o G-proteins, protein kinases and phosphatases, etc.  Second messenger o Small molecules that can be produced or stores of the moleucles like ions of calcium that can be released and go to different parts of the cell o Through second messengers or other Binding of extracellular signal molecules to either cell-surface or intracellular receptors  These will generally be hydrophobic – the messengers are able to pass through the membranes easily to get to the receptors o This is in the case of intracellular receptors  In contrast – with cell-surface receptors you’ll have signaling molecules that are hydrophilic Intracellular receptors  Nuclear receptor super family  They are derived from certain lipid type components, like cholesterol – they can be processed by different enzymes to give you different products  These particular hormonses can be produced within glands, i.e. the adrenaline gland  They can go throughout your blood stream – bee taken up by other types of cells and be recognized by them, they can cross the plasma membrane beuase of thir hydrophobic nature and bind to these enzymes  Different kinds of receptors all have a ligand binding domain Lecture 9 – Basic Principles of Cell Signaling and GPCR System o Sequences to recoznige the hydrophobic molecules Gene activation by a nuclear receptor - Cytoplasmic, intracellular receptor  The hormone Glucocorticoid can enter the cell and binds to the GR (Glucocorticoid receptor)  When it binds to the receptor it bprevents it from binding to another receptor and also inhibits the G from going elsewhere into the nucleus  There are other things, inhibitors, that can inhibiti the receptor and prevents G from binding, allow the G to enter the nucleus  The G binds to the GR which promots the removal of the Inhibitor and the GR complex will dimerize (either in nucleus or cytoplasm)  This then allows for the DNa binding domains to bind the DNA  Activation domains – portions of the proteins that bring in different transcription factors – for this activation domain to work you need the DNA binding region to have them come in to bind the promoter region to give you the genes that you need Basic Concepts of Signnal transduction  Signalling molecule is the primary signal – it will transmit a message through the receptors different comonents  Possibly downstream affector proteins – have effectr proteins effect other effector proteins – they can be cytoskeletal, gene proteins or enzymes perhaps  They can transmit signals to these proteins, i.e. cytoskeletal, which could change the shapre of the cell, or gene expression or directly effect the enzymes within the cell Four forms of intercellular signaling  Endochrine signaling – two cells that are far apart and signaling to each other  Paracrine signaling - two cells that are close togehte rbut not directly touching and contact each other o Nerve cells are a good example of parachrine signaling, they work by paracrine signaling  Autochrine signaling – signal made by the cell itself, goes outside and then is read by the cell  Direct contact signaling – Direct signally, possibly production of a transmembrane protein, compoment of the extracellular matrix – they will bind to receptors on the adjacent side, they are physically connected to each other which allows for cell signaling to occur  You can have different combinations of these – possibly both endocrine and paracrine signaling occurring within cells Signaling by Cell-surface receptors  ½ synthesis and release the signaling molecule by the signaling cell Lecture 9 – Basic Principles of Cell Signaling and GPCR System  3/4Transport and binding the signal to a specific receptor of the target cell (change in the conformation!)  5Initiation one or more intraceullular transduction pwahtways  6a Short term cellular response  6b long term cellular response  7/8 Termination of cellular response  remember rthat you need to turn off the signal o Often there is an auto-feedback to the signal, it is able to promote changes to bring the signal back to the off position Extracellular signals can act slowly or rapidly to change the behaviour of a target cell Animal Cell’s Deendenceon multiple extracellular signal molecules  keep in mind that the cel is always receiving many different ell signals and it has to decide what it needs to do  You can have signals just to survive and chill  Mytogenic signals – survive, take up glucose but at the same time start replicating your DNA – grow and divide  Differentiate – survival signals to self renew but also a signal to stop self- renewing now go make a mature differentiated cell  Trophic Factor withdrawel  Nothing! Don’t survive or do anything, this leads to apoptosis Ligand-receptor interactions  Receptors are very picky about who they bind to – you don’t want” promiscuous” receptors  How to get specificity – therea re certain amino acids on the receptor that has certain charges associated with those amino acids – theres a complimentary, it might be very positively charged perhaps - there’s very specific areas where the proteins interact – the specificity is defined by the actual proteins that participate in the protein protein binding  HAS TO HAVE THE RIGHT CONFORMATION  Has to have a certain number of amino acids that have the right kinds of complimentary charges  Molecular complimentary – is this lock and key necessity  This is an interaction that occurs by non-covalent forces (generally ionic interactions) so that the interactions are not permanent, these are things that kind bind and release  When binding the receptor occurs you generally will get conformation changes – wat will happen is receptors near by will come together because of this and they will “bundle together” and dimerize The dissociation constant Lecture 9 – Basic Principles of Cell Signaling and GPCR System  When talking abou the affinity of a receptor for a ligand have to consider the dissociation constant  AT EQUILBIRUM – sow
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