Signal Transduction: Just as much as we need cell phones, cells need their signal transduction. Between tissues, cells, external environment, like how light is a signal , that is based on a signal on G protein coupled reaction. Our signals don’t necessarily have to be hormones, could be a number of other things. Signals are majoDon't forget about the age old question of sol y viento episode 3
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r way of communicating within the body First, the signal is Received by receptors. Then the signal is amplified. This is why little bit of hormones goes such a long way. You can have about Nano molar concentration of hormones and it will still go a long way. That is not only due to the strong strong affinity of receptors to the hormones but also due to the amplication. The players responsible for providing for signal amplification: - G protein - Signaling cascades - Activation of Kinases and Phosphatases To amplify a signal, focus of a signal is to trigger a cellular response. So how is a signal going to respond to however they’re supposed to respond? And how will the signal terminate? - Often times, signal not terminating can be problematic like in cancer cells, when the signal don’t terminate. - Cell proliferation? - Often times, could be a cause of a disease. Two Outcomes of Signal Transduction Pathways - In this course, we might focus on change of enzyme activity or change in group of enzymes - Signal transduction also can change gene expression. o That happens quite a lot o Signal transduction cascades can also change gene expressions o The result of these signaling cascades are either individual or combinations. What are the signals? - Neurotransmitters o External signals - Hormones and growth factors - Smell, taste, vision o Based on signaling cascades most of which involve a G protein doubled receptor- Extracellular matrix o Very important - Surface to which cells are attached. They are not free floating, they’re either attached to one another or attached to extra cellular matrix. EC matrix provide important signals to the cell and the environment. - The attachment maintains a differentiated state. - Cellular differentiation o What makes a cell specialized. Like what makes a muscle cell, muscle cell and what makes a liver cell, a liver cell. o A lot of that not only has to do with gene expression , but also with ability of cell to interact with the extracellular matrix. o In cancer, you lose some of the differentiated characteristic and cells become much more aggressive. o So, the EC matrix is also another helpful signal, that cells are dependent on. The interactions between cell related protein and the EC matrix General Characteristics *Specificity: - Receptors located in two places plasma membrane of cytoplasm. o The reason we DON’T HAVE steroid hormone in plasma membrane is because: We don’t need to. Steroid hormone is hydrophobic. relatively small in comparison to protein hormones such as insulin, glucagon, etc o Therefore, Steroid hormone can pass through the membrane based on chemical characteristic and the size. o Steroid hormones are INSIDE the cells. o Receptors at the membrane are large, polar, charged - Major difference with interaction with the receptor interaction with its ligands is it’s- relative affinities o Enzymes can stand the range that’s why they have different Km . Whether it’s an allosteric enzyme with K0 or 5, or you’re talking about Michaelis Menten equation. The difference in enzyme structure changes in Km values. o With receptors, they bind with VERY HIGH affinity, the majority of it. They might have low affinity sites but if you want to have the reaction initiated from that particular receptor to be productive, you HAVE to have high affinity and specific. High affinity sites matter the most. *Amplification:Signal reacts with Enzyme one; Enzyme 1 triggers Enzyme 2 has 3 folds; then enzyme 2 activates more enzyme 3; Each of these steps are point of amplification and point of regulation For Example: Epinephrine (muscle) or Glucagon (liver): 1. They interact with their receptor—G-protein. a. Receptor typically has no activity other than to bind the hormone. b. The reason it’s called G-couple protein is coz it’s going to involve G protein. i. It is G-protein that has activity. 1. 3 subunits ii. When hormone binds, G-protein becomes activated 2. One of the subunits split from the other two and go to activate another enzyme- Adenylate cyclase in this case. 3. That enzyme produces 2nd messenger – Cyclic AMP (derived from ATP and its substrate) 4. Cyclic AMP activates Protein Kinase which stimulates another Kinase 5. That another Protein Kinase stimulates enzyme that’s involved in breaking of Glycogen. *Desensitization/Adaptation If a system becomes refractory, can no longer respond for a brief period of time. In conductance of neural impulse, sodium rushes in, trigger the action potential, eventually export Na back out of the cell… You max out on how well you’ll be able to stimulate the cell and still get a response. Therefore, it’s a way to give cells a recovery period so that when another stimulus comes, you can still be able to give a strong response.; in a sense also runs from the feedback. *Integration Hormones integrate with another hormone to turn on/ off a cascade. We’ll focus on 2 types of signaling cascades: 1. G-Protein coupled receptors - Highlighted in Red - A.k.a Serpentine Receptor coz it has 7 α-helices that are integral member proteins that snake in and out of a membrane 2. Receptor Tyrosine KinasesThese are not the only two signalling cascades. We also have Steroid receptor, that translocates to nucleus to change the instruction on binding the steroid hormone. Structure of G-Protein Coupled Receptor (GPCR) Won Nobel Prize for knowing the structure of G protein and how G protein reacts to receptor. Receptor is an integral membrane protein. Integral protein need the lipid environment for the right structure. The functions affected by G-protein coupled signalling cascades are given in the table. The blue belongs to the receptor itself.The ligand binding here is in yellow. The bottom in red, green and yellow is the G protein. It is interacting with receptor by non-covalent interaction, that on binding the ligand (could be hormones, extracellular signals, etc) is going to trigger specific interaction. More about G-Proteins - Quaternary structure i.e. 3 subunits (α,β,γ) - The α subunit has enzymatic activation o Able to hydrolyze GTP; it’s a GTPase o In start, GDP is bound and when GDP is bound, G-protein is inactive. o After receptor binds, GDP comes off and GTP comes on o When α subunit binds GTP, it becomes active and dissociate from β and γ. o When α subunit HYDROLYZE GTP and splits it to GDP and inorganic P, it returns to inactive state. What triggers it’s enzymatic activity? How does G-Protein stay active for certain period of time? How does it know when to terminate? What happens if it terminates the signal too soon? - Membrane mediated events- Adrenaline binds to receptor, GDP comes off and GTP binds - The α subunit detaches and β and γ with it’s own ligand mediator goes with adenylyl cyclase. The α has it’s own ligand mediated channel. - This is a protein-protein reaction when an active α subunit reacts with adenylyl cyclase and converts it’s substrate ATP to cyclic AMP - Cyclic AMP is the second messenger that’s going to relay the signal from membrane to the interior of the cell. About the reaction with Adenylyl cyclase; - Very large enzyme, has multiple α subhelices as it spans the membrane. - Catalytic side faces the inside of the cell because ATP is a substrate and it’s not hydrophobic that would face inside the membrane What does Cyclic AMP (cAMP) do? - Binds to Protein Kinase A @ regulatory subunit, makes catalytic subunit active and change activity of some enzymes. o Protein Kinase A has 2 regulatory subunits and 2 Catalytic subunit How do we turn signal off? Multiple ways of Signal Termination: 1. One way would be to hydrolyze GTP of the G α subunit. The α subunit joins the other two partners and becomes inactive. GTP and GDP here is EXCHANGE…NOT SYNTHESIS. G protein DOESN NOT CONVERT GDP to GTP. One comes off, the other comes on; it’s an exchange. The α subunit can flip the GTP but can’t make it. 2. Phosphodiesterase degrades cAMP Another way except for hydrolyzing GTP would be degrading secondary messengers. Enzyme that degrades cAMP= Phosphodiesterase - They are specific for certain molecules. - cAMP depends on Phosphodiesterase o Enzyme adds water, break the bond that makes cAMP “cyclic” and make AMP AMP could be used to make ADP or ATP. Example: Caffeine inhibits Phosphodiesterase. - You’re depending on G α subunit to terminate it’s signal.- If you overwhelm your system with caffeine that every Phosphodiesterase is inhibited by caffeine, results could be noticeable. Caffeine is also considered to be a drug since it causes such physiological changes. Caffeine is metabolized by cytochrome p450 (also metabolizes tobacco and other environmental components). Some people have single nucleotide polymorphism that doesn’t metabolize caffeine Cholera -Caused by drinking impure water Symptom of cholera: Dehydration There are changes in ion balance. Typically an ion channel is affected. That channel is under control of G-protein & G-protein coupled receptors. Cholera toxin, it ADP ribosylates the G α subunit on an arginine and that prevents the G α subunit from hydrolyzing GTP . The signal stays on i.e. the channel remains open. Na rushes out, it primarily affects the intestines, which is why you have diarrhea, part of the reason why people become dehydrated. 10/21 Glucagon and Epinephrine Purpose of these hormones: - Catabolic hormones o Refers to a breakdown process o **Break down of Glycogen o Glycogen: Polymer of Glucose Store glucose in body, particularly in liver & skeletal muscle ∙ The reason to store glycogen: o After eating, high blood glucose which you won’t be using at the time. o After exercise, you break down glycogen which provides fuel to make ATP o Overnight fast, liver glycogen is broken down to glucose, glucose enters blood stream maintaining glucose homeostasis. ∙ Sometimes, glucose doesn’t go to blood but is taken by muscles for aerobic/anaerobic contraction o What breaks down Glycogen? In Liver, only Glucagon or Epinephrine can do that. ∙ If you’ve fasted for hours and go for run, both hormones would be in your liver. You’d break down lots of glycogen and oxidize your fatty acid. You need energy to function properly and muscle contraction. ∙ You need to maintain glucose homeostasis Muscle ONLY has receptor for epinephrine. Muscle DOES NOT have glucagon receptors. Both muscle and liver has same process of glycogen breakdown, however triggered by different hormones. ∙ Breaking stored fuel to provide energy for muscle (in muscle tissue) or provide energy for glucose homeostasis (in liver). ∙ In liver, glucagon and epinephrine can work together(when fasting for long time and then u start to workout). If only overnight, you’d probably only find glucagon in your blood. G-protein Coupled Receptors (GPCR) Can Signal with Second Messengers other than cAMP - cGMP o Important in Central Nervous System in vision, response to light - Calcium ion - Inositol o The polar phosphate group serves as second messenger o Phosphotyl inositol Polar head group in inositol is gonna be cleaved off so you are left with diacylglycerol backbone, 2 fatty acids Two hormones that work for this cascade in particular; ∙ Vasopressin o Helps control blood pressure o Involved in hemodynamics of circulatory system ∙ Oxytocin o Produced in lactating mammals Both hormones similar in structure and relatively small o o o PIP2 Reason it’s called that coz there’s additional Phosphate in hydroxyl group Tells position of phosphate, #4,5 in inositol groupo The enzyme that cleaves Inositol is Phospholipase-C When cleaved, results in 2 second messengers ∙ Diacylglycerol (DAG) o Still retains hydrophobic characteristics o Stand within membrane ∙ IP3 o In losing inositol, also lost 3rd phosphate that was in the middle o It’s gonna go to cytoplasm o It’s POLAR charged so will definitely go in cytoplasm; won’t even diffuse through membrane. The GPCR-PI Cascade In case of Vasopressin and Oxytocin, - They bind to their receptors - G-protein undergoes exchange - GDP off, GTP on - G alpha moves away, and interacts with phospholipase C (membrane associated enzyme) - Phospholipase C cleaves PIP2 - Diacylglycerol (DAG) stays in the membrane - IP3 diffuses away - IP3 opens channel in ER reticulum and outflows Ca (IP3 receptor binding IP3 and opening Ca would be example of gated ion channel) o Gated Ion Channel open or close in response to a signal. o Here, signal is IP3, binds to a receptor which is a channel and allows Ca to outflow from inside of ER o Two Organelles store Ca in cells: Mitochondria ER - DAG and released Ca activates Protein Kinase C (Phosphorylates other proteins) o DAG can activate partially but for full activation, you need both GPCR-PI cascade is diff as it uses different set of secondary messengers - Not all G-protein cascade goes over cyclic AMP - In this case, G-protein activates Phospholipase C So, two types of G-protein coupled signaling cascades: