Physiology Exam #1 Note Packet. L#1-#8.
Physiology Exam #1 Note Packet. L#1-#8. 0800
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This 26 page Study Guide was uploaded by Denise Croote on Saturday January 23, 2016. The Study Guide belongs to 0800 at Brown University taught by John Stein in Fall 2014. Since its upload, it has received 111 views. For similar materials see Principles of Physiology in Biology at Brown University.
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Date Created: 01/23/16
Denise Croote Principles of Physiology Course Packet Lecture One: Introduction & Homeostasis • For something to become “inside the body” it must be consumed, digested, transported into the blood, and absorbed into the cells • urine is stored in the bladder, but is not technically in the body • need to balance solutes and water before you can absorb nutrients into cells • the reproductive organs serves the species, but not really the individual • intracellular fluid: fluid inside the cells, the cytosol and the fluid in the organelles • interstitial fluid: extracellular fluid that surrounds the cells • plasma: the liquid portion of the blood • Homeostasis: keeping oneself within a tolerable range • Dynamic consistency describes how the body may vary significantly in the short term, but remains fairly constant over time • In a steady state a certain variable (like body temperature) may not be changing, but energy must be added to maintain that steady state • nerve tissue and heart muscle tissue have the smallest range in which they can survive • humans can survive +/- 0.5 on the pH scale • there are more bacteria than cells in the body (some of which are good) • Neurons and endocrine cells have the function of keeping the body within range • The set point is the value the body prefers to be at, and it is compared to the current measure • In a NEGATIVE feedback system, the variable being regulated brings about a response that tends to move the variable in the direction opposite to the original change • Ex.) An increase in body temperature leads to a response that decreases body temperature • Occurs within the cells as well, production of ATP symbolizes a high energy state and the ATP molecules can in turn inhibit the enzymes needed to break down glucose to produce ATP • A POSITIVE feedback system is not as common in nature because it has the potential to take off exponentially • If you were hot, your body would start shivering to generate heat, which would make you hotter and the discrepancy between you and your body temperature larger. This would cause your body to start shivering more which would make the temperature difference even larger • Positive feedback is good in some cases (birth) because muscle contractions stimulate the release of oxytocin, which stimulates contractions, which further stimulate oxytocin release Cell Physiology and Transport: • in order to function cells need the correct environment, pH, nutrient content, and waste removal program, CO2 is important in the body to regulate pH • a lot of waste is generated at the mitochondria (big transition of CO2 and Oxygen) • sugars, fats, and proteins are used to make energy • all organelles have a cell membrane, which: • is a barrier between chemicals inside and outside the cell • sets the electrical gradient • has phosphate head groups and phospholipid tails that are aligned towards the insides of the cells Denise Croote • the hydrophillic heads like the water environment and the hydrophobic tails form the fluid inside (its lipid character serves as the barrier) • if you are polar you need protein channels (ex. Aquaporins for water) to get through the membrane • as you move closer to our skin, the cell membranes are less permeable to water so that fluid does not escape • some proteins span the membrane and others are located on the surface • proteins that are involved in receptor reactions (like g protein coupled receptors) are clustered near the membrane • The membrane is a lipidy insulator and the cholesterol interferes with the fluidity • If you increase the cholesterol in the membrane the membrane will become less fluid because it serves as a “stiff raft” that things cannot move around • a glycoprotein is a glucose unit bound to a protein, the levels of carbs attached to a membrane can determine functionality and help in identification • Diabetes: when blood sugars is too high, the circulating glucose can attach to proteins and cause damage to cells and blood vessels, the high levels of sugar also cause neuron death Lecture Two: Cell Physiology and Transport Continued • In a cell, proteins do most of the work (the transcription and the translation ect.) • use 20 amino acids to build all of the proteins (1000s of amino acids linked together) • the proteins could be polar, nonpolar, and ionized • figuring out how primary structure folds into its 3D configuration is difficult, but we know that certain sequences fold into helixes and others pleats • functional domains can contain amino acids that are thousands of units apart • whatever factors affect shape will therefore affect protein function • essential amino acids: body can’t synthesize them so we need to obtain them through the diet • nonessential amino acids: body can synthesize them, but it’s also good to get them through the diet • disulfide bonds weld parts of the proteins together, van der waals forces, ionic bonds, and hydrogen bonds also give shape • Quaternary proteins subunits are labeled alpha, beta, gamma • Diffusion: works for molecules that are able to cross the membrane, which means they must be small and lipid soluble, do not need a protein to carry them across • Ion channels: formed by one or several proteins that congregate and allow ions to diffuse across the membrane • Carrier mediated transport: used to transport ions that are too large diffuse (amino acids and glucose ex.)) are transported with proteins • net flux describes the gain in solutes in one compartment and the loss in solutes in the other compartment one per unit time • diffusion goes high concentration to low concentration • you do not need to invest ATP, but all of the particles have their own random thermal motion, which is the temperature that is required for the particles to move • it is expensive to keep our bodies at the right temperature to foster diffusion, so indirectly there is energy involved in diffusion • higher temperature means the particles are moving faster which means they will diffuse more rapidly • greater surface area means more can diffuse, smaller molecules can diffuse faster • particles cannot travel very far in a straight line because they undergo so many collisions, therefore the circulatory system is necessary to bring molecules directly to the tissues Denise Croote • cells of the cornea do not amount an immune response because little diffusion occurs there, they located very far from capillary cells • Flux = PA (Co- Ci) • A stands for the surface area of the membrane, (Co-Ci) represents the concentration gradient, and P stands for the permeability • Permeability differs for each molecule at a certain temperature and it relates to the ease a particle moves through a given membrane • the larger the permeability the faster the flux (many molecules can travel faster in water than in a lipid membrane) • most of the absorption that results from swallowing a pill occurs in the small intestine • if something can be absorbed in the stomach, it is more controlled The normal pH of the body is 7.4 and the pH of the stomach is 1.0 – 2.0 • the gradient for the H+ ions goes into the cell because a difference of 5 on the pH scale correlates to 100,000 ions • the ration of H+ for the cell to stomach is 1: 100,000 • in the stomach A- is more likely to associate with an H+. The HA can then travel across the stomach membrane and into the cell. The lower concentration of H causes the HA to dissociate and now the A- cannot cross the membrane to leave the cell. • the stomach has a higher concentration of H+ and the cell has a higher concentration of A- • we do not notice drastic changes in pH because we have buffer systems, amino acids can pick up H+ when needed • Ion channels are usually 4 subunits or greater • they can differ in levels of selectivity, some can be barely selective, or others very selective • maybe only one ion can go through a channel or maybe all ions of the same charge will go through • the selectivity is based on channel diameter, the charged and polar surfaces of the proteins in the channel, and the shells of hydration associated with the ions • channels aren’t like tubes that you throw a marble through, the molecule interacts with the sides of the channel as it moves along, the channels can even change shape as the molecule moves through • the movement of an ion is based on the concentration gradient and the electrical difference across the membrane • the electrical difference describes the membrane potential (difference in charge across the membrane) that may pull and ion or push an ion a certain direction • The electrochemical gradient is dependent on a balance of both of these forces • channels can be opened or closed at any time (gated) and the opening and closing can be stimulated by a ligand, mechanical stretching of the membrane, or voltage changes in the membrane potential • in a water environment a Na+ ion is surrounded by the negative oxygen component of water • an ion channel works by systematically plucking away water molecules and replacing the charges with charges in the walls of the channels • can separate ions by size because a Na+ ion knows how tightly it should be surrounded, therefore it does not fit through a K+ channel because it cannot interact with the walls of the channel • for facilitated diffusion there is no energy involved, a molecule moves down its gradient BUT it needs a shuttle because the molecule is not very permeable • molecule may be too big to diffuse across the membrane (like glucose GLUT transporters) • this method is NOT as efficient as ion channels because the transporter can become saturated and competition for the transporter can occur Denise Croote • molecules follow their downhill gradient, and diffusion stops when equal numbers of molecules are binding to the outer surface of the transporter to get in and the inner surface of the transporter to get out • specificity, saturability, and competition all explain why these two processes are relatively slower than simple diffusion and movement through ion channels • active transport : selective, relatively slow, need to use ATP directly or use a process that involves ATP elsewhere • best example of primary active transport is the sodium potassium pump • High concentration of K+ inside the cell and low concentration of K+ outside the cell. High concentration of Na+ outside the cell and low concentration inside the cell • ATP comes along and binds the channel in the cytoplasm, changes the shape of the channels so 3Na+ ions fit well, they move across the membrane, release, and channel shape has a high affinity for 2K+ ions, they transport across, release and the phosphate group is removed • best example of secondary active transport is the movement of glucose • transport of Na+ down its gradient is coupled to the transport of another molecule • the transporters that do this have two binding sites, one for the ion (typically Na+) and the other or the co-transported molecule) • Solute can be thought of entering the cell by “piggy back” • ATP is not used directly, but ATP is used to set up the Na+ gradient that is used Other means of transport across the membrane: • pinocytosis: internalization of liquids • phagocytosis: internalization of solids, like bacteria • secretory vesicles: used to release contents into the extracellular space, fuse the vesicle membrane with the plasma membrane • synaptic vesicles: used to release NT into the cleft Lecture Three: Osmosis & Transport • osmosis describes the movement of solvents • moles/liter or 6.02E23 molecules/liter • water is the solvent because it is usually the most abundant substance • Osmolarity takes into account how that molecule behaves in a solution • Ex.) glucose stays as a unit in solution but NaCl will dissociate into two osmoles • osmoles: how many particles a molecule breaks into. • when water (solvent) moves, it causes volume shifts • addition of a solute causes the concentration of water to decrease relative to that of pure water • osmotic pressure: recorded in mmHg or ATM. To measure osmotic pressure of a solution we compare our system to a vacuum System: • low concentration on the left (fewer solutes and more water molecules), high concentration on the right (more solutes and less water) • a semi-permeable membrane will let water go down its gradient, water moves from left to right and pushes the water level up on the right. • Air molecules above the open tubes (1 ATM) push down equally on both sides, the difference in concentration gives rise to a difference in height • we can measure the difference in height in inches of water or we can put an extra force (mmHg) on the higher volume and measure how much force it takes to push down on one side to make the volumes equal Denise Croote • If you have salt water and regular water you could push the water out of the salt solution and into the chamber with pure water, this takes a great deal of force but is used in lieu of wells by people who live near oceans Osmotic pressure = iMRT = ∆CRT • i = van’t Hoff factor • M = molarity (moles/liter) • R = (0.08206 L*atm/mol*K) • T = Temp (deg K) • RBC thrown into a dilute solution will swell because water will flow down its concentration gradient and into the cell. The volume inside the cell will increase, the concentration of the solutes inside the cell will decrease, and the cell will equilibrate • normal concentration of solutes inside a cell is 300 milliosmoles/liter • if you put that cell into a solution of 299 milliosmoles/liter water will flow into the cell because the concentration of solute is higher inside and exert a pressure on that cell • delta C = 1 milliosmole/liter or 0.001 osmoles/liter, R = 0.08206 and T is 310K • Can find the osmotic pressure using the formula osmotic pressure= ∆CRT • even small gradients can create significant pressure on the walls of the RBC, but the design of the RBC allows them to swell and shrink • when dealing with RBCs, if water goes into the RBC we assume the concentration of the extracellular fluid does not change significantly because it is so much larger when compared to the RBC • Tonicity: will a cell swell, shrink, or not change at all • Isotonic: a solution that does not change a cells volume, the solution contains 300mOsmol/L of non-penetrating solutes (like proteins) • when talking about tonicity we are talking about non-penetrating solutes. If a solute can go across the membrane it will distribute across the membrane equally and not contribute to the gradient • Hypertonic: a solution that causes water to leave the cell and shrink. The solution will contain a greater concentration ( like 600 mOsmoles/liter) • The volume will shrink by ½ because if you put the same # of solutes in half the volume, we will reach 600 • Hypotonic: a solution that causes cell to expand, The solution will contain a lower than 300omoles for liter, so water will rush into the cell • Iso-osmotic does not always equal isotonic • For osmotic we are looking at all solutes, doesn’t matter if they penetrate or they do not penetrate . • Filtration: fluid going from the plasma to the interstitial fluid • Absorption: fluid going from the interstitial fluid to the plasma • nutrients are exchanged, waste is washed out, pH is regulated at the capillary beds • we want to keep our plasma within a tolerable range for proper circulation Denise Croote • in the plasma 3L is plasma and 3L is red blood cells • if you start with 6L but bleed out 2L you don’t have enough volume to push blood up to your brain, blood volume drops, and blood pressure drops st • 1 thing to happen –interstitial fluid shifts into the blood stream to compensate • glucose, amino acids, salts can all penetrate the wall, but plasma proteins do not cross • 90% of the volume is re-absorbed into the blood vessels and capillary, 1% is re-absorbed in the lymphatic • The osmotic pressure in the capillary is due to the proteins that do not penetrate the capillary bed • under normal circumstances the proteins are not permeable, under diseased states they are sometimes permeable • capillaries are filled with plasma and located in beds of interstitial fluid • higher concentration of protein in the blood plasma, meaning there are fewer water molecules in the plasma and more water molecules in the interstitial fluid • water goes from the interstitial fluid into the capillary bed to swell the capillary (that’s what we don’t want – we want the plasma to filter out) • The pressure in the capillary is blood pressure, at the beginning of the capillary bed, the blood pressure is greater than the opposing colloid osmotic pressure and water moves from the plasma to the interstitial fluid (filtration) • As the blood travels through the capillary the blood pressure starts to drop and colloid osmotic pressure wins out and fluid goes into the plasma from the interstitial fluid (absorption) • 99% of what is filtered gets re-absorbed (normal cross over point) • If your blood pressure drops at the beginning of the capillary bed, you will not get the filtration and you will automatically get the absorption and suck interstitial fluid into the blood vessels • If you put more fluid into the blood pressure, your blood pressure will be brought back up • exocrine is dumping outside the body (sweat, salivia, digestive enzymes from the stomach) • In the lumen of a sweat gland you are still outside the body • endocrine is dumping things inside the body (glands) • dumping into interstitial fluid • solutes will be secreted and water will follow to give you the bulk of the solution • looking at the lumen of the kidney, which is outside the body, and the inside of a cell which is inside the body • apical membrane is facing the lumen, basolateral membrane is facing the inside of the body • Tight junctions do not let solutes and water sneak through • To get inside the body you must be transported across the apical membrane • the chances of you getting through the digestive track without being absorbed are minimal, we have evolved a digestive system that gets every last molecule of glucose into our body • inside the cell you usually have high glucose, glucose has to go up a concentration gradient to go from the lumen and into the cells • we get glucose in by co-transporting with sodium • Sodium has a concentration gradient to go inside because there is a lot of salt in the gut (what you eat + the stomach and pancreatic secretions are salty), and because an electrical gradient, the inside of the cell is negative with respect to the outside, pushes Na+ in • called a symporter or cotransporter • secondary active transport because there is no ATP being used on site, ATP is being used to maintain the sodium gradient down at the basolateral membrane, being used to pump K i+ and Na+ out (which is primary active transport) Cystic Fibrosis: • symptoms: failure to gain size, salts sweat, thick membrane (respiratory) Denise Croote • not good to lose salt because it is harder to replenish salt than it is water • CF transmembrane regulator proteins – regulate movement of Cl across the membrane • located within the cells lining the exocrine glands (sweat glands, airways, pancreas) • to form sweat, we secrete sodium and chloride into the lumen of the sweat gland and water follows • normally, as sweat goes up the neck of the gland it is impermeable to water, but Na and Cl are re-claimed so that the sweat comes out on the surface with a lower concentration of salt • if you can’t transport the Cl back in, sodium transport can’t occur either, so more salt lands in your sweat • In order to secrete into a duct, the GI tract, or an airway we typically secrete mucus • CF patients can’t get the Cl out of the body, and therefore can’t get the Na out of the body, and water does not follow into the mucus, leading to overly thick secretions that will clog airways and lead to infection • amino acid 508 occurs in the nucleotide binding domain, removal of amino acid 508 does not destroy function as a chloride channel, but causes a slight change in the protein shape that is enough to cue the channel to be destroyed in the cell as “abnormal” • if we could get this channel from the ER to the membrane without being destroyed we would be able to restore function • How do we get this channel to the membrane? • introduce chaperonin molecules that bring the channel to the plasma membrane more efficiently • we can compensate for loss of sweat by drinking things like gatorade, the respiratory and digestive issues are the ones we need to address • Antibiotics disrupt the osmotic gradient • Antibiotics kill bacteria by disrupting their cell wall • the cell wall protects the bacteria by acting as a structural barrier that prevents the bacteria from rupturing if placed in a hypotonic solution • gramicidins poke holes in the membrane of bacteria to allow water and solutes through Lecture Four: Cell Communication • nervous system and endocrine systems are the major communicators for the body • gap junctions – intimate, connect two cells and allow fluid and solutes to travels between them • surface protein interactions – proteins on one cell can bind to the protein receptors of another cell (common for cells that are neighbors) • chemical messengers – for closer distances, chemicals at synapses are used to communicate and for longer distances hormones are used. • Autocrine – cell releases a chemical messenger and it binds to itself • Paracrine – chemical messenger can diffuse and bind to cells nearby (diffusing distance) • Endocrine System: • dumping a chemical messenger into the interstitial fluid or the circulatory system • can reach every cell in the body • cells must express the receptor, any cell with the receptor will be acted on • slower because it relies on the blood stream to carry the message, must go through capillaries, veins, heart ect. (can take 10s – 10min) • The levels of growth hormone will go up and down over years Denise Croote • It is a “broadcast message,” which is good if you don’t need a fast response but want a wide audience • Nervous System: • Makes more specific & discrete connections • use electrical impulses to cover distance, much faster, you can get a message from one side of the body in less than a second • you can segregate which cells respond and which do not Classes of Chemical Messengers: • amines – dopamine, nor-epinephrine, epi (same synthetic pathway), serotonin, histamine • amino acids – are packaged and released and then recognized by receptors, only recognized as neurotransmitters, not hormones • would not work as hormones because we obtain amino acids through the diet and if glutamate was a stimulatory hormone (like adrenaline), then eating would cause your heart to race, muscles to twitch ect. • amino acids are used at synapses and all cells bind and bring in amino acids • in the nervous system, cells change their responses if high concentrations of amino acids are present • peptides – most pituitary hormones are peptides, synthesized by transcription/translation, can be used as NTs or hormones • acetylcholine – combination of choline and acteyl – CoA • Choline is ingested dietary and Acetyl- CoA is found in the entry way to the mitochondria • Ach is used as the major output NT from the CNS (a motor neuron leaving the CNS will innervate skeletal muscles, the ganglia of the sympathetic and parasympathetic, and heart muscle using Ach) • Ach neurons die during the early stages of Alzheimer's and boosting Ach is a common therapy early on • some people think that mental acuity will benefit from taking supplements to boost Ach, the thought was to give people choline, since the body has excess Acetyl CoA, so people would have sharper memory • No evidence that it affects people for the good • sometimes if you give big doses of a drug the body responds by shutting down its enzymes in the presence of the excess • steroid hormones – all derived from cholesterol, all derived from the same starting point, sex hormones, testosterone, cortisol • side effects of taking steroids: if you naturally produce these hormones at certain levels and you take supplements that triple the concentration of the hormone, your body responds by downregulating its response (maybe decreasing receptor #/effectiveness) • nitric oxide (NO) - is a messenger and a gas, synthesized in the body, it affects tissues, it has a half life of around 3 seconds, only diffuses a short distance, freely diffuses through cell membranes • discovered NO by finding the enzyme that synthesizes it, nitric oxide synthase • discovered NO has an effect on the CNS and blood vessels • Ligand – could be a steroid, amino, NT, hormone • Ligand is released, binds to a receptor, receptor undergoes a conformational change, elicits a response in the cell • Could be a gated ion channel that opens or closes • Could trigger a response, like a cascade, that leads to the production of second messengers Denise Croote • Key Terms to Understand: • Receptor: can be located on a plasma membrane or inside a target cell to bind a messenger • Specificity: the ability to bind one or a limited number of chemical messengers • Saturation: the degree to which receptors are occupied by messengers • Affinity: the strength with which a messenger binds • Competition: the ability of different molecules to compete with a ligand for binding to its receptor (usually structurally similar) • Antagonist: a molecule that competes with a natural ligand and does not elicit the response • Agonist: a chemical that binds the receptor and mimics the natural response • Down – regulation: a decrease in the number of receptors, may occur as a result of over production of a certain chemical • Up – regulation: an increase in the total number of receptors, could result from a low concentration of chemical ligand • Increased sensitivity: increased responsiveness of a target cell • Affinity: measured by the concentration of the messenger, and the response we get • Low affinity – high concentration of the drug will give you a lower response • High affinity – same concentration gives you a much larger response • a competitor binds to the receptor but does not activate the receptor, gives you a decrease in responsiveness • a low affinity and high affinity drug could have a similar chemical structure and be recognized by the same 3D shape of the receptor • Maybe one binds with a higher aggressiveness, maybe it stays bound longer • the competitor binds either at the binding site or elsewhere and it decreases activation by either preventing binding or preventing binding from causing the same response • many times one ligand has different receptors • Ex.) nor-epinephrine in the blood has different effects on different tissues. If it binds to blood vessels in the kidney, it causes them to constrict and decrease blood flow, but if it binds to the heart it causes dilation and increase in blood flow • different ligands will activate the same second messenger system through different receptors • if a messenger is freely permeable, you don’t need a receptor on the cell surface, the receptor is either in the cytoplasm or the nucleus • if you are synthesizing a lipid soluble messenger, it is not easy to store them, you just increase or decrease the activity of the enzymes that makes them • are able to upregulate or downregulate genes that are involved in transcription and translation (this takes longer, 10s of minutes to hours) • for plasma membrane receptors • First messenger binds on the outside of the cell to cause a change • Second messenger is intracellular and can move around and affect other proteins • opening an ion channel immediately changes membrane potential • Ca 2+ is a very special ion, the normal concentration of Ca 2+ in the cell is very small, when channels open, Ca 2+ enters and acts as a second messenger • there are proteins that recognize the change in Ca 2+ (release of NT, muscle fibers ect.) • for most ions, the concentration does not really change when you open up a channel • G Protein Coupled Receptor • g protein coupled receptor is attached to a g protein (on the intracellular side) • when the first messenger is not present, the receptor is coupled to the g protein • Binding of the first messenger initiates a conformation change in the g protein receptor that causes a change in shape of the g protein • allows GTP to bind the alpha subunit and activate it Denise Croote • When GTP binds, alpha separates from the B,y subunit and both entities interact with local proteins • Alpha subunit activates an effector protein (could be a channel or enzyme) • binding of an alpha subunit can cause an effector protein to crank out more product • g proteins have 7 transmembrane spanning regions • removing GTP will cause the alpha and the B,y to re-associate (turning off) Pathway #1 • activated alpha subunit binds to adenylyl cyclase • adenylyl cyclase takes ATP, rips off phosphates, and puts them into a cyclic conformation (cyclic AMP) • cyclic AMP is the second messenger and it interacts with PKA (protein kinase A) • PKA binds to a protein and phosphorylates it • Takes a phosphate group from ATP and puts it onto a protein, which will change the function of the protein • rip phosphate off (dephosphorylation) ends the activity of the protein • (Downfall) the more steps you have, the more chances there are for something to go wrong • there are multiple levels at which the system can be tweaked • Ex.) you can have G stimulatory or G inhibitory proteins • Benefits: 1.) Amplification, Modulation, Duration • What kinds of responses can you get? 1. Opening an ion channel 2. Inserting or removing ion channels 3. Modulating transcription 4. Affecting metabolic factors 5. Lipid and glycogen breakdown Pathway #2 • activated g protein activates Phospholipase C • PLC rips the phospholipid apart to get IP3 (phosphate head) and DAG (lipidy tail) • IP3 goes to the ER and triggers the release of Ca 2+ into the cytosol • Once Ca 2+ gets in the cytosol it binds to proteins, changes function, and causes response • Ca2+ activates PKC (protein kinase C) to phosphorylate proteins How can you have different responses from activating the same second messenger systems? • BECAUSE The cell is divided into compartments and machinery holds it together • g proteins can activate adenylyl cyclase or phospholipase C • Whichever one gets activated depends on which is closest to the g protein that is activated • Other minion proteins keep adenylyl cyclase and PLC close to the g proteins Lecture Five: Nervous System • Dendrites receive input and stick out of the cell body • The output is the axon, typically one axon leaves the cell body • The axon carries and electrical input down to the terminal (mm or meters long) • Electrical signal does not dissipate, causes release of NT to pass the signal on to the post- synaptic cell Denise Croote Challenges for Neurons: • For a liver cell sending nutrients or proteins to the cell membrane is easy because it is a short distance • For neurites – translation occurs in the soma and proteins must be transported long distances. Whether you are a synthesis enzyme or a transporter you must be shipped along the cytoskeleton • Molecules walk along the microtubules using ATP to carry products to the end • When the health of neurons is compromised, it is the long projecting neurons that are the first to show symptoms (the neurons that go to the toes and the fingers) • You have neurons that are sensory neurons (receptors for a stimulus – could be pressure receptors, stretch of digestive tract, concentration of oxygen/ions, light hitting retina) • After receiving sensory input, CNS must send a message to a muscle or a gland and tell it how to act (motor response) you usually either move or secrete • For the most part, the CNS dictates what comes about of sensory input • Electrical and chemical messages alternate (electrical conduction causes a 2 messenger to act) until they reach the target • Able to send messages within milliseconds • If a message needs to be sent quickly you can increase the speed of the impulse by making the electric cable (axon) larger in diameter, or you could increase the insulation by myelin. Myelin allows you to skip many millimeters of axon and skip from node to node. • The blood brain barrier is positioned where ever you have a capillary inside the brain, 99% of brain is protected • Neurons get nutrients from capillaries, the barrier is between the plasma inside the capillaries and the interstitial fluid outside of neurons • The barrier is the astrocytes (type of glial cells) that wrap around the capillaries and tightly regulate what gets through • Neurons are “high maintenance” they are very sensitive to pH, oxygen, sugar, temperature, and ion concentrations • This makes it tricky to get things into the brain..i.e.) if you have an infections it will be difficult to get white blood cells into the brain • Membrane potential is an electrical potential (difference in charge across the membrane) • It is like a battery that is used to do work (bacteria, viruses all do this as well) • Excitable cells use this to carry information • Neurons and muscles have rapid changes in membrane potential • The inside of the cell is negative with respect to the outside • Even though textbook images only show positives on the outside and negatives on the inside, this is actually inaccurate, there are several positive and negative charges inside and out. The difference occurs at a more localized level, charges line along the inside of the membrane and feel each other since the membrane is so thin • It takes very few extra positive charges outside and extra negative charges inside to create the -70 membrane potential • Cells pump 3Na+ out of the cell and 2K+ into the cell, by doing this you are charging up a sodium and potassium battery, making it so that Na+ will rush in and K+ will rush out • However, pumps can’t pump fast enough for neurons to function • If you make the cell permeable to K+, K+ will flow out and Vm will become negative • If you make the cell permeable to Na+, Na+ will flow in and Vm will become positive • In order to get the membrane potential to jump quickly we need to open ion channels (much faster) • All neurons pump K+ in one direction and Na+ in the other, so that IF the channels are open the gradients will already be established and ready to change Vm • Extracellular Na+ = 140 …. Intracellular = 12 Denise Croote • Extracellular K+ = 5 …. Intracellular = 150 • After one AP, the intracellular Na+ goes from 12 to 12.0000001. It barely budged, because each ion has a significant weight and you do not need a lot of charge to move to generate a change in membrane potential • Potassium battery is more powerful than the sodium battery Scenario #1: • If we have Na and Cl in a channel with a permeable membrane, Na and Cl will diffuse until the concentrations reach equilibrium on both sides of the membrane • If we have Na and Cl on equal concentrations in a beaker separated by a membrane and we attach a battery, Na+ will flow to the side of the channel with the more negative charge • If we have our same beaker and we only let Na+ cross the membrane its chemical gradient will drive it in one direction and charge will build up on that side. The electrical gradient will build until it balances the chemical gradient and reaches electrochemical equilibrium. • In this scenario, relatively few Na would have to go through the channel to get the electrical potential to change. • You can balance all concentration gradients with equal and opposite electrical gradients. You could also get sodium to go backwards up its concentration gradient if you applied enough electricity. Scenario #2: • Let’s say we have another beaker with more 10XNa/Cl on the left than on the right. We need 61mV positive on the right to prevent the flow of Na. If you make the gradient steeper, chemical gradient would be larger than the electrical gradient and ions would flow to the right. • E ion = RT ln [ion] out • zF [ion]in Eion = Nernst Potential R= Gas Constant T= Temperature Z= Valency of ion F= Faraday’s Constant • Simplifying the formula gives us E ion = 61mV ln [ion] out • [ion]in • For sodium the membrane potential is 61mV because ln(150/15) = 1 • If the membrane is at the Nernst Equation for the ion, the ion will not move • If you open up sodium channels, the equilibrium potential would trend towards +61mV • For potassium the equilibrium potential is -80 mV. The negative sign just shows you the direction. This means that the concentration gradient is in the opposite direction, and when K+ channels open the membrane will go negative • Current is the movement of (+) charge • V=IR • I=gV where g is conductance or the ability for something to move (ex.) thick tube has a high condutance vs. thin tube) • V describes the driving force on that particular ion and g describes the # of open channels • I = g(Vm – Eion) • When there is no driving force, there is no net current • E ion remains constant, because the pumps are always churning in the background to make sure Na doesn’t build up after several action potentials for ex. • Vm changes dramatically, as the membrane potential dances, the driving force on ions changes with it Scenario #3: Denise Croote • If we have a membrane potential of zero and we open a K+ channel, the gradient on K+ is larger in magnitude and the membrane potential will shoot towards -80. The more channels we open the faster the membrane potential will shoot down until it reaches the membrane potential for K+ • As the membrane potential becomes more negative, the driving force for K+ gets smaller in magnitude so the slope gets smaller as well and the graph asymptotes at -80. • The same thought process occurs if we are dealing with Na+ channels • If you start your membrane potential at zero and you open one Na+ and one K+ channel, the membrane potential will go negative because the driving force for K+ is larger (difference between Vm and Ek is bigger than the difference between Vm and ENa) • As the membrane potential gets closer to EK the driving force for K gets smaller and the driving force for Na gets larger • If you open up 1Na+ and 5K+ channels the same thing will happen but the membrane will be closer to Ek because of the larger K+ conductance • As the membrane gets more negative, the rate of K+ leaving slows down and the rate of Na+ entering balances, which is called steady state. Review: • We can restate a concentration gradient in electrical terms because it is the gradient of a charged particle • The Nerst Equation tells you the membrane potential at which there is no net movement of a certain ion • The direction the membrane potential is draw towards when channels open is based on ion permeability and the current membrane potential in relation to the Eion • Permeability is a measure of the weight something will carry • The theoretical upper and lower limits for the membrane are +60 (from pure sodium) and -80 (from pure potassium) Scenario #4: • Two factors to consider: equilibrium potential and conductance for Na+ and K+ ions • Membrane potential stars at zero and we open 1Na+ and 10K+ channels • The driving force on potassium is greater than the driving force on sodium when the membrane potential is at zero. We also have a greater conductance because more K+ channels are open. • Ik = gk (Vm-Ek) > INa = gNA (Vm-Ena) • K+ leaves more rapidly than Na+ enters, the membrane goes in a negative direction, increasing the driving force on Na+ but decreasing the driving force for K+ • The sodium current increases and the potassium current decreases until they reach a steady state (closer to Ek) • This is NOT equilibrium, we still have K+ going out and Na+ going in, but the rate of INa is equal in magnitude to IK • Anything that changes conductance will change where the steady state lies. • Leak channels: there are a bunch of ways sodium and potassium can get across the membrane (leak channels, Na+ co-transport with glucose) • RT/zF reduces to 61mV • GHK equation tells you the membrane potential based on the relative permeability of sodium and potassium. • Log of anything greater than one is positive, and less than one is negative. If you weight potassium permeability more, Vm will be more negative because it incorporates the log of a number less than one. If Na is weighted more, Vm will be more positive because it incorporates the log of a positive number Denise Croote • For Cl- (since it has a negative charge) you would have to flip and have concentration in over concentration out • It’s the RELATIVE permeability between sodium potassium that is the most important • Under normal conditions, concentrations of ions do not change and permeability is dependent on the number of channels open for each ion. There is more potassium leak then sodium leak so Vm is at -65mV when resting. • Different cells have different membrane potentials, depending on the concentrations of ions and the permeability. Some cells could have a resting potential of -75 mV (could be due to more closed sodium channels or more open potassium channels) Lecture 5a: Action Potential Axon Potential: • takes 1-2ms, which explains why this must be due to voltage gated channels rather than the activities of pumps Membrane potential starts at -65mV (resting) due to leak channels o Leak channels are constantly present o Sodium leak and potassium leak are steady here so membrane potential doesn’t change Initiating the axon potential: In an axon, current from a prior segment of the action potential depolarizes the following segment of the axon to activate the voltage gated Na+ channels. If the channels are closer to the cell body, ligand gated channels will open at the synapse and Na+ will enter to cause the initial depolarization. You can also depolarize the membrane mechanically. Mechanical stretch could allow for positive ions to enter the cell. Stage One: depolarization – membrane potential goes to zero because Na+ is entering the cell. Na+ current is bigger than K+ current. o iNa > iK because voltage gated Na+ channels open. Stage Two: overshoot - membrane potential goes past zero and approaches the equilibrium potential for Na+ o Driving force on K+ is huge at the peak. Driving force on Na+ decreases. Stage Three: repolarization – membrane potential goes negative. K+ leaves the cell. K+ current is bigger than the Na+ current. o For motor neuron action potentials potassium leak channels are open, not voltage sensitive channels, which is why you don’t get the hyperpolarization o For other action potentials, voltaged gated ion channels are involved • Action potentials carry info, are all or nothing firing events, and are the same size. • Action potentials are separate from one another; you cannot generate another action potential until you bring the membrane negative again and reset the voltage gated sodium channels. • Voltage gated sodium channels: • Have 4 different subunits and selectivity for the geometry of Na+ • Can be closed, open, or inactivated and have sensing mechanisms that change channel conformation in response to voltage changes. • Closed open inactivated closed • When membrane potential overshoots, the Na+ channels are forced into the inactivated state. The sodium cannot enter. Denise Croote • To de-inactivate the channel, you HAVE to swing all the way back to the closed state. You need to repolarize the membrane to negative values (via potassium leak outward), this insures that APs don’t depolarize and bounce around at membrane potentials around zero • This gives us an absolute re-fractory period • Voltage gated sodium channels are examples of positive feedback loops, initial depolarization opens Na+ channels, which further depolarizes the membrane, and opens more Na+ channels. • Threshold describes the amount of depolarization that must occur to initiate the positive feedback loop. • Once the channels are pushed into the open state and depolarize, they immediately shut themselves off (like a safety gate – only open for a split millisecond so the positive feedback loop is not taken advantage off). Voltage Gated Potassium Channels: • depolarization of the membrane gets both the sodium and the potassium membranes to swing open, but the voltage gated potassium channels take longer to open • Also called delayed rectifers and they repolarize the membrane • voltage gated K+ channels are negative feedback related Action Potential Diagram: 1. Rest: Pk = 10, pNa = 1 (starting leak permeabilities) 2. Rising: Pk = 10, pNa = 1 + 10 (voltage gated Na+ channels) 3. Falling: Pk = 10 (leak) +10 (voltage gated potassium channel), pNa = 1 4. Resting: Pk= 10, pNa=1 if there were no delayed rectifyers, the membrane potential would take much longer to repolarize because everything would be dependent on the leak channels • subthreshold events are graded, the bigger the stimulus the bigger the depolarization. • Once you start firing action potentials and the stimulus is above threshold, you cannot differentiate between the stimuli • We do not communicate by graded potentials because they cannot transmit information over large distances • The frequency of action potentials, tells us how strong the stimulus is Conduction and Synapses • Current is the movement of charged particles, K+ is the most common positive ion that is free to move • Positive charge accumulating in one area will induce a chain reaction whereby positive charged will be kicked down the axon • We don’t have diffusion of ions all the way down axons. • Current diminishes with distance, because axons are not very good conductors of electricity • We need action potentials (big electrical events) to compensate for dissipation of charge • We need to regenerate the action potential as it moves down the axon in order for it to arrive at the end of the terminal • Graded potentials diminish quickly with distance and do not reach the axon hillock • Current will take the pathway of least resistance • To do this we need to promote the passage of current through axons and increase the resistance to current flow through other avenues • Voltage gated sodium channels are located right next to the cell body, these channels decide when to fire an action potential by fostering depolarization past threshold Denise Croote • Integration: describes how thousands of synapses act on a cell at once (inhibitory and excitatory) and their combined efforts determine if a cell reaches threshold • Once we generate an action potential it’s an all or nothing event, it propagates and ends at the terminal with all its strength. • The site where the action potential occurs has a positive membrane potential, Na+ comes in and half of the current goes one way and half of the current goes the other way. • The membrane right behind the action potential has voltage gated Na+ channels that are inactivated, so an AP will not propagate in the other direction • The membrane ahead of the AP has available voltage gated Na+ channels • Current doesn’t just travel down the axon, it leaks out as well • Current travels down the INSIDE of the axon quickly, this is faster than waiting for voltage gated sodium channels to open and current to flow in • A mylinated axon will minimize the loss of current so it can maximize the amount of current that travels through the axon • How do we make more current travel down the inside of the axon and less current travel down parallel pathways? • Charge will not travel through the membrane, because the membrane is a phospholipid bilayer and charge does not cross it easily. • Current will be lost through leaky Na+, K+ channels, we use myelin to minimize this leakage • We separate nodes, forcing the current to skip farther down, but if the node is too far away you will have failure • There is a current in the extracellular fluid that opposes the direction of the action potential. The AP leaves the membrane slightly depolarized and the membrane behind the AP is slightly negative so the current will travel backwards from positive area to negative area. How to increase efficiency: • maximize the intracellular flow by increasing axon radius to decrease internal resistance • increase the resistance of the membrane, we do this by having no open ion channels between nodes • decrease the capacitance of the membrane by myelinating it • Because the membrane is just a few phospholipid molecules thick, the charges inside and outside can feel each other. Thus the membrane is a capacitor. The closer the positive and negative charges are (the thinner the membrane is) the more charge that capacitor can store. The better the insulator the more charge the capacitor can store. • The phospholipid bilayyer introduces a difficult challenge, because when the current comes in it charges up the capacitance of the membrane. We want to decrease the capacitance of the membrane • Myelin does this by increasing the distances between the two conducting media, as distance increases, the charges on each side of the membrane do not interact nearly as well. • If you demylinate, a lot of membrane is exposed and capacitance increases, decreases the amount of current that makes it to the next node. This will terminate a portion of the action potentials. One of the major symptoms is weakness. The CNS will send 100 action potentials to the muscle neurons and the muscle neurons will only be able to conduct 50 of them. The brain wants a stronger force than the muscle can deliver. • The heavier the layer of myelin and the thicker the diameter, the farther we can spread our nodes, decreasing nodes will increase conduction velocity (150m/s) • Thin unmyelinated axons will only be able to conduct at 0.5m/s • You cannot have all of the axons conduct at 150m/s because space is a resource, and because the bigger the axons the higher the metabolic demand will be, movement via diffusion will also be slower when the axon is bigger Denise Croote Fluid Model: • We essentially have an RC circuit; we have a resistive pathway down the inside of the axon and a capacitive pathway in parallel. The current can either go down the inside, or it can charge up the capacitor. • V=IR • If we inject fluid into a hose, the pressure on the inside goes up, that pressure initiates flow from that location, the flow will go from high to low pressure • Some fluid will leak out of the tube (like it would leak out of the channel) • Capacitance could be modeled by “stretching” of the tube • If we had a glass tube, water would just shoot down the hose, but if the hose is a stretchy material, then flow will be impeded by the energy it takes to stretch that hose • Wrapping an axon with myelin is equivalent to wrapping duct tape around the hose to make it less stretchy • The purpose of the myelin is to decrease capacitance, NOT to plug up ion channels. Communication at Synapses: • An action potential depolarizes the axon terminal • The depolarization opens voltage gated Ca2+ channels and Ca2+ enters the terminal • Ca2+ binds to docking proteins on vesicles and triggers fusion of the vesicle membrane with the plasma membrane • NT diffuses and finds a receptor on the post-synaptic cell • If you have ten action potentials per second these steps will repeat ten times Lecture 6: Nervous System Organization • Medulla – house keeping functions, keeping you breathing properly • Pituitary – involved in the endorcrine system • Hypothalamas – controlling body temperature • spine is the vertebrae that are stacked on top of each other • in humans we stand upright and the spine serves as a column, there are a lot of things that could go wrong with the back because vertebrae in humans hold more weight than is typical for animals • Once you get outside the spinal column, you can see that just to the right and to the left you have sympathetic chain ganglia Peripheral Nervous System: 1. Afferent (sensory) 2. Efferent (motor) • Somatic motor describes skeletal muscle, voluntary movement, reflexes • Autonomic motor system describes cardiac muscle, smooth muscle, glands • Sympathetic – fight or flight • Parasympathetic – rest and digest • There is a sympathetic and parasympathetic tone. Systems are always on, but can be turned up or turned down. 3. Enteric Nervous System (Gut) – has a lot of neurons Motor neurons leaving the CNS will release Ach onto their target tissue o Somatic motor neurons: release Ach onto muscle o Parasympathetic neurons and sympathetic neurons: release Ach onto ganglia outside the CNS Denise Croote Sympathetic ganglia are right along the spinal cord Parasympathetic ganglia are further out towards the target tissue The ganglia are obligatory synapses. The neurons from the CNS that innervate them are pre-ganglionic neurons and the neurons that leave the ganglia and go to the targets are post-ganglionic neurons All pre-ganglionic neurons release Ach onto Ach receptors The postganglionic of the sympathetic nervous system release nor-epinephrine The postganglionic of the parasympathetic nervous system release Ach but onto a different variety of Ach receptors In the heart, sympathetic innervations release NE, speed it up the heart and increase the strength with which the heart contracts (gas pedal) Increased parasympathetic activity slows heart beat and decreases the strength with which it contracts Why speed it up and slow it down? Why not just have a pedal to go fast and you either press it or you don’t. Why do we drive around with one foot on the gas and one on the break? o If we want the car to go faster, we could step on the gas and off the break. This allows us to modulate both resting tones. Parasympathetic neurons have muscarinic Ach receptors o these are G protein receptors Sympathetic neurons use Adrenergic receptors o Has several receptor subtypes: alpha1,2 and beta1,2 o During fight or flight you cut off blood flow to the peripheral and pump it to the muscles o The heart muscles (with Beta receptors) will dilate to increase blood flow and the kidney’s (with alpha receptors) will constrict to limit blood flow Somatic NS has neurons that release nicotinic Ach receptors on skeletal muscles The Autonomic Parasympathetic has N-Ach receptors in the pre-ganglionic neurons and the M-Ach receptors for the post ganglionic neurons The Autonomic Sympathetic has N-Ach receptors in the pre-ganglionic neurons and NE receptors for the post-ganglionic Denise Croote Denise Croote Lecture 7: Endocrine System Endocrine glands: the pituitary, thyroid gland, adrenal glands are the most well know. The stomach is also a gland because it secretes hormones that get picked up by the blood stream and sent to the brain to control feeding behavior Peptides: Undergo transcription and translation via ribosomes
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