Lecture 8 CSF Cell Communication 2024 (1).pdf

tyrosine kinase receptor - JAK STAT pathway http://www.xvivo.net/illustration/ Hi!! I’m Alexandria Biosci 107 Class rep: AM Stream I am doing Health Science as a pre-med course. A bit about me: I am the oldest of 3 siblings, I love going to the beach and watching movies, as well as spending time wit...

tyrosine kinase receptor - JAK STAT pathway http://www.xvivo.net/illustration/ Hi!! I’m Alexandria Biosci 107 Class rep: AM Stream I am doing Health Science as a pre-med course. A bit about me: I am the oldest of 3 siblings, I love going to the beach and watching movies, as well as spending time with the people I love. Contact details: Email: [email protected] Instagram: @biosci107_2024 Excited to meet and help all of you this sem! Kia Ora BIOSCI 107! My name is Myscha – Your 4pm stream Class Rep A bit about me: I'm from Tauranga, I graduated last year and I am studying BioMed (hoping to get into Med) Get in touch with Alexandria and I through messaging our BIOSCI107 Insta My Contact Details: Email: [email protected] Insta: @myschabarry_ I look forward to helping you guys out this year! QR Code for our BIOSCI107 Instagram: Lecture 7 recap…. Lecture 8: How Cells Communicate Learning objectives: 1. describe the overall method of cell signaling 2. describe, compare and contrast the two major cell surface receptors (G Protein coupled and ligand-gated ion channel receptors) 3. describe signal transduction via a phosphorylation cascade 4. describe the role of the two main secondary messengers (cAMP and Ca2+) 5. give examples of cellular activities as outputs of cell signaling Objective One Why do cells communicate? http://beingabiologist.blogspot.co.nz/2011/04/talking-cell.html Cells need to be able to respond as a cell, and as part of a whole tissue They respond to signals from other cells and from the environment These signals are often chemical (but can also be light, taste, smell etc) Objective One Secreted signals can be local or long distance Local signaling: Signals act on nearby target cells growth factors such as fibroblast growth factor – FGF1 (paracrine) Neurotransmitters such as acetylcholine – ACh (synaptic) Can act on the signaling cell (autocrine) Long distance signaling: Signals act from a distance Hormones secreted from endocrine cells travel via circulatory system to act on target cells eg. insulin secreted from pancreatic beta cells enters bloodstream and travels and is detected by various body cells. Objective One Cell signaling : Three main steps During the transduction pathway multiple proteins may be activated, typically via phosphorylation This is a very simplified and generalized view of the process! Objective One Most eukaryotic cell signaling involves: 1. RECEPTION Signalling protein (primary messenger) binds to a receptor protein Results in shape and/or chemical state change in the receptor protein 2. TRANSDUCTION Altered receptor activates a another protein, eg G-protein/adenylyl cyclase The activated protein (often an enzyme) may cause a relay of changes Relay molecules known as “second messengers”, eg. cAMP, IP3 Multiple other proteins may be activated Each activated protein causes a series of changes, this is often via phosphorylation – known as a phosphorylation cascade 3. RESPONSE All of the activated proteins cause one or more functions to occur in the cell This is where the cell actually does something https://commons.wikimedia.org/w/index.php?curid=12081090 CC BY-SA 3.0, details not examinable!! Objective One Receptors are specific! The human body will simultaneously send out many different chemicals and molecules, all aimed at eliciting specific responses BUT only the target receptors will interact with that signal (ligand) and use it to activate signal transduction pathways. Where does this specificity come from? 3D molecular shape of the proteins involved …..structure determines function….. Q: would you eat soup with a fork? Exquisite control is possible: Only certain cells at certain times will have particular receptors (ie. dynamic), meaning that while the signal might be widespread the transmission of the signal occurs only where it is needed. Objective One Receptor location Receptors for water soluble molecules are membrane bound eg. G Protein Coupled Receptor, Receptor Tyrosine Kinase, ligand-gated ion channel Receptors for lipid soluble molecules are not membrane bound Can be located in the cytoplasm or inside the nucleus eg. lipid soluble hormones such as testosterone, estrogen, progesterone, thyroid hormones bind to receptors within the cytoplasm and move to nucleus as a complex We will focus on membrane bound receptors Objective Two G-protein coupled receptors (GPCRs) Transmembrane proteins – pass PM 7 times Hundreds of different GPCRs exist Many different ligands Diverse functions: eg. development, sensory reception (vision, taste, smell) Associated with many diseases (and Nobel prizes!) The target for 1/3rd of modern drugs GPCRs couple with G proteins - G proteins are molecular switches which are either on or off depending on whether GDP or GTP is bound (GTP: guanosine triphosphate, similar to ATP) Campbell Fig 11.8 Objective Two G-protein coupled receptors (GPCRs) Conformational changes determine function At rest, receptor is unbound and G Protein is bound to GDP. The enzyme is in an inactive state. Activated G Protein dissociates from receptor. Enzyme is activated to elicit a cellular response Ligand binds receptor, and binds the G protein. GTP displaces GDP. The enzyme is still inactive. G Protein has GTPase activity, promoting its release from enzyme, reverting back to resting state Shape alters in step 2 but not evident in cartoon GTPase activity : GTP is hydrolysed to GDP and P Objective Two Ligand gated ion channels/receptors These channel receptors contain a “gate” Binding of ligand (eg neurotransmitter) at specific site on receptor elicits change in shape channel opens /closes as the receptor changes shape Ions can pass through channel (eg. Na+, K+, Ca2+, and/or Cl−) Receptor – a molecule/protein which responds to a specific ligand Ligand – a signalling molecule that binds specifically to another protein Ion channel – membrane protein through which specific ions can travel Ion channel receptor – membrane protein through which specific ions can travel, in response to ligand binding (also known as ionotropic receptors) More in CP module Objective Two Ligand gated ion channels/receptors…….. At rest, ligand is unbound and gate is closed. Upon ligand binging, gate opens, specific ions can flow into cell. Following ligand dissociation, gate closes, back to resting. Q. Which body system relies heavily on ligand gated ion channels? A. The nervous system: – released neurotransmitters bind as ligands to ion channels on target cells to propagate action potentials (refer ET:N lectures) Campbell Fig 11.8 and 11.5b Objective Three Signal Transduction Pathways Signals relayed from receptors to target molecules via a ‘cascade’ of molecular interactions A typical phosphorylation cascade: Protein kinases are enzymes that transfer a phosphate group from ATP to another (specific) protein. Typically, this activates the protein. Series of protein kinases each adding a phosphate to the next kinase Phosphatases are enzymes that dephosphorylate (remove the phosphate) rendering the protein inactive, but recyclable Typically, it is serine or threonine residues that are phosphorylated. This means that mutations affecting these residues could be detrimental. (link to lecture 9) Objectives 3&4 Use of a second messenger - cAMP Sometimes another small molecule is included in the cascade, these are second messengers. eg. cAMP and calcium ions cAMP in GPCR signalling: (No - you don’t need to know these details) Recall earlier GPCR slide, plus: The activated enzyme is adenylyl cyclase Activated adenylyl cyclase converts ATP to cAMP cAMP acts as a second messenger and activates downstream proteins, for example, PKA which phosphorylates other proteins Campbell 11.12 This pathway is disrupted by cholera toxin! Refer CP lectures Objectives 3&4 Calcium is a widely used second messenger Low [Ca2+] inside cell (typically ~100nm) Very high [Ca2+] outside the cell (more than 1000-fold higher) Maintenance of concentration via calcium pumps is important -out of cell -into ER -into mitochondria Objectives 3&4 Ca2+ and IP3 in GPCR signalling Here, the activated protein is phospholipase C which then cleaves PIP2 (a phospholipid) into DAG and IP3 IP3 diffuses through cytosol and binds to a gated channel in the ER Calcium ions flow out of ER down concentration gradient and activate other proteins towards a cellular response Campbell 11.14 Muscles use Ca2+ to contract - refer to ET:M lectures Objectives 3&4 Why so many steps? Amplifies the response Provides multiple control points Allows for specificity of response temporal spatial despite molecules in common Allows for coordination with other signaling pathways Image by Max Pixel CC 0 Objective Four Cellular Responses include: Examples of a cellular response include activation or regulation of: Gene expression Alteration of protein function to gain or lose an activity Opening or closing of an ion channel Alteration of cellular metabolism Regulation of cellular organelles or organisation Rearrangement/movement of cytoskeleton A combination of any of these The transduction of a signal leads to the regulation of one or more cellular activities Objective Four Turning off the response is important!! All of the signals are for a limited time: activation usually promotes the start of deactivation, so that signalling is of short period of time, ensuring homeostatic equilibrium. it means the cell is ready to respond again if required cAMP is broken down by phosphodiesterase (PDE) wired after coffee??? caffeine blocks the action of PDE Inhibition of specific PDE’s can also be a therapeutic approach eg Viagra - inhibits a specific cGMP-degrading PDE Objective Five An example – a fleeing impala 12th campbells figure 11.1 Objective 4 and 5 More detail – adrenalin stimulation of glycogen breakdown epinephrine =adrenalin Adrenalin acts through a GPCR, activates cAMP and two protein kinases in a phosphorylation cascade Results in active glycogen phosphorylase which can convert glycogen to glucose 1-phosphate Amplification means that 1 adrenalin molecule can result in 108 glucose 1-phosphate molecules! Campbell 11.16 Objective Four Sometimes its useful to generate a lot of ATP quickly!! Glycogen is a long term energy store in liver and skeletal muscle glycogen breakdown results in glucose 1-phosphate glucose 1-phosphate is then converted to glucose 6-phosphate which can then be used in glycolysis to generate ATP Wikimedia Commons CC BY 2.0 But - receptors can be deceived…. Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the coronavirus (SARS-CoV-2) surface spike glycoprotein (S protein) Here, ACE2 in our respiratory tract is the lock, and the S-protein on the virus is the key https://www.youtube.com/watch?v=jkNxmTrrZSk&feature=emb_err_watch_on_yt If you want to see more: https://xvivo.com/examples/how-covid-19-mrna-vaccines-work/ https://vaccinemakers.org/ An overview…please watch as part of your revision…. This video is also available in Canvas On the CSF module page https://mediaplayer.pearsoncmg.com/assets/apf-mech-hormone-action 4:48 minutes Specifics in this video not mentioned in the signalling lecture are not examinable but it brings together several concepts from 107 lectures so far that you are expected to understand. Remember we want you to be able to link the information together that you are learning. eg. Homeostasis, endocrine system, hydrophobic/hydrophilic, plasma membrane other useful resources for this lecture All video links are on my CSF module page in Canvas Details in this video are examinable Signalling overview.mp4 (is on canvas modules page for this lecture ~1min), very basic Source: Pearson animation, Campbells text Khan academy video of about 6 minutes you might find useful https://www.khanacademy.org/science/biology/cell-signaling/modal/v/example-ofsignal-transduction-pathway Specifics not stated in lecture are not examinable Next CSF lecture: Gene to Protein Tip: try to watch the video on my Module page in Canvas BEFORE Lecture 9 (protein synthesis ~2.4m) https://www.youtube.com/watch?v=gG7uCskUOrA Publisher permission was granted for lecture slide use of images/resources from the 107 texts (Tortora and Campbell). Unless otherwise stated content was sourced from these texts or were lecturers own