Cell and Cellular Environment Student 2023.pdf

The Cell & Cellular Environment Brianna Hanson, PA-C Intro to Pathophysiology Summer 2023 Topics Cell Membrane Cell Transport Cell Adhesion Cell Metabolism Cell Communication Fluid Movement & Balance Basics of Buffers & Acid-Base Balance Equilibrium Equilibrium Rate of formation of products = rate o...

The Cell & Cellular Environment Brianna Hanson, PA-C Intro to Pathophysiology Summer 2023 Topics Cell Membrane Cell Transport Cell Adhesion Cell Metabolism Cell Communication Fluid Movement & Balance Basics of Buffers & Acid-Base Balance Equilibrium Equilibrium Rate of formation of products = rate of formation of reactants No net energy expenditure Steady state / dynamic equilibrium Steady State Remains constant over time, but to do so requires energy expenditure 0 system remains constant over time Dynamic equilibrium same if youtake something away from product Adding more reactants will push the system to create more products Adding more products will push the system to crease more reactants Removing products will push the system to create more products (resulting in a decrease of reactants) Removing reactants will push system to create more reactants (resulting in a decrease of products) Catalysts o act as enzymes the catalystsdecreases work inooled to make reactants t produce Catalysts brings starting materials I Catalysts Enzymes act as catalysts in the human body Image Credit: Khan Academy Osmosis Occurs when molecules of a solvent (water) crosses a selectively-permeable membrane in a way that equalizes the concentrations of solute within a solution on either side of the semipermeable membrane No energy is required solvent solvent creates solute Osmoles One (1) mole of any matter has 6.022 x 1023 molecules 1 mole of NaCl has 6.022 x 1023 molecules 1 mole of glucose has 6.022 x 1023 molecules Osmole is different than a mole Osmole describes the number of moles in a compound that contribute to the osmotic pressure of a solution 1 mole of glucose is 1 osmole glucose is a single molecule 1 mole of NaCl is 2 osmoles (1 from Na and 1 from Cl) Osmolality vs osmolarity Osmolality whet we use in medicine # of osmoles of solute Kilogram (kg) of solvent O staysthe same Osmolarity # of osmoles of solute Liters (L) of solvent o changes over time Tonicity vs osmolality They are not the same thing. A solution’s osmolality is determined by the total concentration of all the solutes present. A solution’s tonicity is determined by the concentrations of only those solutes that do not cross a selectively-permeable membrane. We will return to this concept… Concentration gradient “Against Ice concentration gradient” with the concentration gradient “Down at concentration gradient” requirehelp means positive Electrochemical gradient Non-charged molecules are subject to gradients established by their concentrations on either side of a semi-permeable membrane Charged molecules are subject to gradients established by their voltage in addition to their concentrations. They can work in opposition to each other. Knowledge check #1 In 1-2 minutes, define as many of the following terms as possible: Dynamic equilibrium Catalyst Osmosis liter y tonicity Osmolality, osmolarity, Electrochemical gradient 1kg charged non charge molecules like enzyme speed up Catalyst recetia Osmosis deals with water TL; DR: chemistry refresher Human body is a tub of chemical reactions. Reactions can be “free”. Many require energy expenditure. Osmosis  molecules of solvent cross a selectively-permeable membrane such that the concentrations of solute equilibrize across the two sides. Tonicity of a solution is determined by the concentrations of only the solutes that do not cross a selectively-permeable membrane. If able, solutes will move “down” their concentration gradients when separated by a selectively permeable membrane. They want to move in a way that equally distributes their molecules. This doesn’t require energy expenditure. Solutes can be moved “up” their concentration gradients but it takes energy. If a molecule of a solute is charged this concept also applies to the overall charge gradient (voltage) across the selectively-permeable membrane. It will freely move “down” its electrical gradient but moving “up” the electrical gradient requires energy expenditure. This is the electrochemical gradient. Cellular membrane Composition Function Homeostasis Homeostasis Self-regulating process by which internal biological systems maintain stability while adjusting to changing external conditions Cell membrane permeability It is selectively-permeable Impermeable to most water-soluble substances and charged ions Notable exception to the above is H2O Permeable to many lipid-soluble substances; CO2 and O2 important ones Anything that is not inherently permeable through the cellular membrane must have help to get through Cell membrane functions Maintenance of intracellular environment Maintenance of gradients (chemical and electrochemical) Protection Cell activation / communication Transport Cell to cell adhesion Cell membrane composition Lipids Comprised of fatty acid chains (and other things) Proteins Comprised of amino acids Phospholipids Phospholipid bilayer Cellular membrane proteins Highly differentiated Play specific roles Cellular membrane proteins Cellular membrane proteins - integral Facilitation of transport in or out of the cell Cell communication Catalysts for reactions that otherwise would not happen at all or happen too slowly Cell-cell adhesion Cell-cell identification/recognition Image Credit: Nature Education 2010 Cellular membrane proteins Membrane proteins are tightly controlled and adjusted in response to external (and internal) cues They can be Upregulated Downregulated Desensitized Internalized Cellular membrane proteins Proteins have a lifespan They get tagged for destruction Influenced by external factors such as heavy metals, temperature, stress Knowledge check #2 List as many functions of integral membrane proteins as you can recall. TL; DR: cell membrane Cell membrane is a phospholipid bilayer that maintains the distinction between the internal and external cellular environments Function is due to the chemical properties of the bilayer (hydrophobic tails and hydrophilic heads) that allow diffusion of non-polar substances but (mostly) not to polar substances Proteins on/in the membrane perform important functions like transportation of polar substances, cell adhesion, cell signaling. All of these processes can be influenced by external / environmental factors resulting in disease states. Membrane Transport Passive transport Active transport Membrane transport Exchange of molecules through the plasma membrane Passive Active Secondary Active Facilitated Diffusion Simple Diffusion Co-transport Osmosis Endocytosis Exocytosis Phagocytosis Pinocytosis Hypertonic Isotonic Hypotonic Receptor-mediated endocytosis Membrane transport Exocytosis Out Endocytosis In Phagocytosis Solids (mostly) Pinocytosis Liquids (mostly) Membrane transport - passive Diffusion Non-polar substances Small polar substances Facilitated Diffusion Transport Uses transport proteins protein Polar substances need help Osmosis Movement of water through semipermeable membrane NO energy needed Membrane transport – facilitated diffusion passive transport More Channel Integral proteins that have a pore via which ions may cross from one side of membrane to the other Gated channel Ligand, or mechanical, or voltagegated Binding/voltage causes the gate to open or close Carrier protein Binding of specific solute leads to conformational change which allows movement across membrane Less Membrane transport - active Pumps Na/K pump Cotransport Carrier Requires energy Membrane transport - pumps Sodium / Potassium Pump Sodium has a higher extracellular concentration Potassium has a higher intracellular concentration Bringing in sodium produces ATP to power bringing in potassium Net + charge outside cell Image Credit: Wikipedia Membrane transport – secondary active Energy derived from “stored” energy as opposed directly from the breakdown of ATP Brings other substances into cell against their concentration gradients Image Credit: Bio Ninja Resting membrane potential (RMP) Electrochemical gradient across cell membrane Established by membrane pumps and channels Neurons fire thanks to RMP Muscle contract thanks to RMP Knowledge check #3 Briefly outline the mechanism of the sodium-potassium pump. TL; DR: cell transport Transport can either be passive or active Active transport requires energy Active transporters can fuel other transporters in the form of stored energy Maintaining the extracellular and intracellular environments through transport mechanisms is vital to a number of biological functions Potassium gradient (and to lesser degree sodium) as established by the sodium potassium pump is essential for the resting membrane potential Disruption of transport mechanisms can result in clinical disease / disorders Cell adhesion Extracellular matrix Cell-adhesion molecules Specialized cell junctions Cell adhesion mechanisms 1. Extracellular matrix 2. Cell-Adhesion Molecule (CAM) 3. Specialized cell junctions Extracellular matrix Extracellular matrix (ECM) Molecular network creates structure and support for cells Participates in regulating cell growth Comprised of: Basement membrane Glycoproteins / proteoglycans Non-proteoglycan polysaccharides Interstitial Proteins matrix Minerals Extracellular matrix Glycoproteins / proteoglycans Helps to store growth factors Helps to hydrate cells Contributes to tensile strength of tendons, ligaments, cartilage Cell-cell adhesion (fibronectin) Non-proteoglycan polysaccharides Hyaluronic acid – absorbs water Proteins Collagen – provides tensile strength Elastin – allows for stretch Extracellular matrix Fibroblasts Most common cell type in connective tissue Secrete components of the ECM (certain types of collagen, fibronectin, proteoglycans) Extracellular matrix Basement membrane Part of ECM Sheet-like lining that separates epithelium and connective tissue 2 layers  basal lamina and reticular connecting tissues Fibrillin and microfibrillin help to connect those layers Cell-adhesion molecules (CAM) Cell membrane proteins 4 different families: Cadherins Selectins Ig Superfamily Integrins Mechanical attachment between cell and ECM Specialized cell junctions Desmosomes – physical attachment Tight Junctions – barrier Gap Junctions – allow cell to cell transport Knowledge check #4 Turn to your neighbor. Talk through what you both recall about the extracellular matrix (ECM). Think about the components and the functions of the ECM. TL; DR: cell adhesion ECM is a complex matrix with many components that provides scaffolding support to nearby cells and participates in regulation of various cellular functions Basement membrane separate epithelial tissue from connective tissue Cell-to-cell adhesion occurs via CAMs and specialized cell junctions Cell to ECM adhesion is accomplished via CAMs (Integrin) Cell metabolism Anabolism Catabolism Cellular metabolism ATP is created from chemical energy contained in organic molecules: Carbohydrates Lipids Proteins Used in synthesis of organic molecules, muscle contraction, and active transport Functions as a way to STORE and TRANSFER energy Cellular Metabolism omaking stuff ATP is needed Catabolism Anabolism Glycolysis Oxidative decarboxylation (pyruvate) Citric acid cycle Oxidative phosphorylation Makes Energy ATP Amino acid biosynthesis Glycogen storage Gluconeogenesis Requires Energy cellular respiration CO2 Cellular metabolism Cellular metabolism – phenylketonuria Decreased activity of phenylalanine hydroxylase (enzyme) Converts phenylalanine to tyrosine Elevated levels of phenylalanine leads to developmental delay, behavior issues, seizures Req’s dietary changes, so no: Soybeans Shrimp Chicken Legumes Aspartame TL; DR: cellular metabolism Metabolism = catabolism (creates energy) + anabolism (uses energy) Glycolysis, oxidative decarboxylation, TCA, oxidative phosphorylation are processes that create ATP Acids and carbon dioxide are also created via metabolic pathways Amino acid biosynthesis, glycogen storage, gluconeogenesis, and a nearly infinite number of other cellular processes require that ATP Dysfunction in metabolism can result in profound disease Cellular communication Cellular messengers and receptors First and second messengers Signaling cascades Hormonal communication Cellular messengers Also called chemical messengers How cells transmit messages to other cells They are created in response to a specific stimulus and travel to a target cell in order to elicit a response from that cell In the nervous system, they are called neurotransmitters In the endocrine system, they are called hormones In the immune system, they are called cytokines Categories of cellular messengers Endocrine Uses blood stream to send signals far away Paracrine Local action Influences nearby cells Autocrine Cell secretes a chemical messenger that binds to its own receptors Juxtacrine Cell-to-cell contact-dependent Regulation of messenger release Cellular messengers are secreted In response to an alteration in the cellular environment To maintain a regulated level of certain substances or other hormones Cellular messengers are regulated by Chemical factors (i.e., calcium levels in the blood) Endocrine factors (i.e., thyroid stimulating hormone) Neural factors (i.e., autonomic stimulation of pancreas) Feedback loops are used to maintain homeostasis Copyright © 2019, Elsevier Inc. All rights reserved. 62 Regulation of messenger release Negative feedback loop neuro go lone Long short Most common Ubiquitous in the endocrine system Positive feedback loop Uncommon Examples: Contractions during childbirth Stimulation of milk production Trigger of ovulation Copyright © 2019, Elsevier Inc. All rights reserved. 63 Cellular messenger transport Messengers (hormones) are released into the circulatory system by endocrine glands and distributed throughout the body. Water-soluble hormones circulate in free, unbound forms. Lipid-soluble hormones are primarily transported bound to a carrier or transport protein. Copyright © 2019, Elsevier Inc. All rights reserved. 64 Cellular messenger receptors Target cells Recognize and bind with a high affinity to (specific) hormones Initiate a signal The more receptors, the more sensitive the cell Copyright © 2019, Elsevier Inc. All rights reserved. 65 Cellular messenger receptors Are located in or on the plasma membrane or in the intracellular compartment of the target cell Water-soluble hormones (Most) cannot diffuse across the plasma membrane Lipid-soluble hormones Easily diffuse across the plasma membrane and bind to cytosolic or nuclear receptors Copyright © 2019, Elsevier Inc. All rights reserved. 66 Cellular messenger receptors Copyright © 2019, Elsevier Inc. All rights reserved. 67 Cellular messenger receptors Up-regulation Low concentrations of hormones increase the number of receptors per cell. Down-regulation High concentrations of hormones decrease the number of receptors. Copyright © 2019, Elsevier Inc. All rights reserved. 68 Effects of cellular messengers Three cellular responses to messengers 1. Act on preexisting channel-forming proteins to alter membrane channel permeability 2. Activate preexisting proteins through a second messenger system 3. Activate or suppress protein synthesis Copyright © 2019, Elsevier Inc. All rights reserved. 69 Lipid-soluble messengers Ligand (lipid-soluble) Protein Target Transport Protein Generates a response Signaling cell Target cell Non-target cell 70 Lipid-soluble messengers Lipid-soluble messengers are often made on-demand because they cannot be stored Are synthesized from cholesterol Examples Sex hormones, steroids, vitamin D, retinoid, thyroxine, arachidonic acid derivatives Activate Ribonucleic acid (RNA) polymerase Deoxyribonucleic acid (DNA) transcription Water-soluble messengers Ligand (water-soluble) Receptor Generates a response Signaling cell Target cell Non-target cell 72 Water-soluble messengers Water-soluble 1st messengers Extracellular molecules Initiate signaling pathway Interacts with a receptor Examples: peptides, glycoproteins, polypeptides, amines 2nd messengers Intracellular molecules Activated by 1st messenger In turn, activate kinases that lead to cellular response Water-soluble messengers 2nd messenger activates response within the cell Activates G-protein to produce primary effector Hormone messenger) binds to membrane bound receptor (1st Primary effector leads to creation of 2nd messenger 74 G protein-coupled receptor (GPCR) Image Credit: 2002 Nature Publishing Group Li, J. et al. The Molecule Pages database. Nature 420, 716-717 (2002) Cyclic AMP – second messenger GPCR activates the enzyme adenylyl cyclase This converts ATP to cAMP cAMP goes on to illicit a cellular response 76 Calcium – second messenger Calcium is kept low in the ICF It is stored in the endoplasmic reticulum (ER) Calcium can be increased via releasing ER stores or letting calcium from ECF into the ICF GPCR are just one way that first messengers cue the calcium second messengers Increased concentrations of calcium in the ICF can cause Neuronal activation Muscle contraction Lots of other things! 77 Proteolytic cascades Coagulation Cascade TL; DR: cellular communication Ligands bind to receptor on/in a target cell to elicit a response. There are various terms given to forms of communication based on distance traveled from signal cell to target cell Lipid soluble messengers target intracellular receptors; act to activate or suppress protein synthesis Water-soluble messengers (1st messengers) interact with membrane-bound receptors on a target cell; activate 2nd messenger intracellularly via methods such as cAMP and Ca++ (both of which use GPCR as an intermediate) Signal transduction and amplification is an important function of proteolytic cascades. Important proteolytic cascades include apoptotic, complement, and coagulation Fluid movement and balance Total body water Movement of water from plasma to interstitial fluid Movement of water from interstitial fluid to intracellular fluid Tonicity and effects on water movement Total body water (TBW) Approximately 60% of the adult human body is water Percentage varies depending on age, muscle mass, and amount of adipose tissue TBW infants > TBW adult > TBW elderly The greater amount of adipose tissue the less TBW Total body water t everything inside outside cell TBW = intracellular fluid (ICF) + extracellular fluid (ECF) 2 3 113 Interstitial Fluid (IF) Lymph Intravascular Fluid Plasma Transcellular Fluid 2/3 of TBW ICF 1/3 of TBW ECF Saliva CSF Pancreatic fluid Peritoneal fluid Pericardial fluid Sweat Urine Biliary fluid Hepatic fluid Synovial intraocular Total body water TBW maintained within narrow range Concentration of electrolytes varies across discrete compartments This is highly regulated and dependent on the function of the fluid Fluid balance & movement - (plasma interstitial fluid) Fluid balance & movement - (plasma interstitial fluid) Capillary hydrostatic pressure (CHP) Mainly determined by blood volume and blood pressure Pressure forces movement of water OUT from capillary and into to the interstitial space anything Capillary oncotic pressure (COP) Mainly determined by amount of protein in the plasma within the capillary Albumin main protein that contributes to this pressure Pressure attracts water from the interstitial space INTO capillary that raises reduces cap pressure Oncotic pressure is not interchangeable with osmotic pressure. Oncotic pressure is a form of osmotic pressure that is from colloids (large MW substances) oncotic will rezymin pressure Fluid balance & movement - (plasma interstitial fluid) Interstitial hydrostatic pressure (IHP) Pressure forces movement of water OUT of the interstitial space and into the capillary Interstitial oncotic pressure (IOP) Pressure attracts water from the capillary INTO the interstitial space Fluid balance & movement - (plasma interstitial fluid) Capillary hydrostatic pressure works in opposition to interstitial hydrostatic pressure Capillary oncotic pressure works in opposition to interstitial oncotic pressure Amount of force each one generates are not equal Balance of these forces tips the scales for moving fluid into the interstitial fluid (filtration) or out of it (reabsorption) Fluid balance & movement - (plasma interstitial fluid) How much water fills into interstitial A Net Filtration (NF) = (CHP+ IOP) – (COP+ IHP) IOP is not a main contributor because there are not many proteins within the interstitial space (oncotic pressure is low) IHP is not a main contributor because lymphatic vessels are continually absorbing water within the interstitial space (hydrostatic pressure is low) Fluid balance & movement - (plasma interstitial fluid) Net Filtration (NF) = CHP – COP cop Fluid balance & movement - (plasma interstitial fluid) oxygen blood w water Fluid movement & balance (IF Movement of water between ICF and IF mainly due to osmotic forces Most abundant cation in the ECF is sodium; most abundant anion is chloride Most abundant anion in the ICF is potassium; most abundant anion is phosphate ICF) Fluid movement & balance (IF ICF) Volume of fluid in the ICF is highly impacted by the concentration of sodium within the ECF Not enough sodium in the ECF will drive water into the cells (this is called hyponatremia) Too much sodium in the ECF will pull water from the cells (this is called hypernatremia) Kidney and various hormones are responsible for maintaining sodium concentration Fluid movement & balance - tonicity Fluid movement & balance - tonicity Fluid movement & balance - tonicity TL;DR: fluid movement & balance TBW is dependent on multiple factors but kept within a narrow range TBW is 2/3 ICF and 1/3 ECF ECF is comprised of many different compartments. Interstitial fluid and plasma are important in fluid movement and balance CHP forces water out from the capillary into interstitial space COP is mainly determined by amount of albumin. It attracts water from the interstitial space into the capillary. IHP forces movement of water out of the interstitial space and into the capillary. IOP attracts water from the capillary into the interstitial space. Net filtration across a capillary (from plasma into the interstitial space) = CHP – COP Movement from between IF and ICF is mainly due to osmotic forces. Sodium is the most abundant cation in the ECF. Potassium is the most abundant cation in the ICF. Isotonic changes occur when changes in the TBW are accompanied by a proportional change in concentration of electrolytes. If a cell is in a hypertonic solution, water will move out of the cell and into the extracellular fluid. The cell will shrink. If a cell is in a hypotonic solution, water will move into the cell and out of the extracellular fluid. The cell will swell. Buffer systems Function of a buffer Carbonic acid – bicarbonate buffer Acids and bases in the body Acids are molecules capable of donating a proton (aka hydrogen ion, H+) Acids are a byproduct of metabolism (endogenous) Lactic acid Sulfuric acid Phosphoric acid Carbonic acid (in the form of CO2) Acids can be ingested (exogenous) Household cleaners (sulfuric / hydrochloric acids) Acids and bases in the body Bases are molecules capable of accepting a proton (aka hydrogen ion, H+) Bases are a byproduct of metabolism (endogenous) Bicarbonate (in the form of CO2) Bases can be ingested (exogenous) Antifreeze Buffer systems stopsph from rising falling or Homeostasis is maintained within a narrow range of pH Enzymes, necessary for metabolic processes, lose efficacy or stop working outside of this narrow pH range Direct cellular injury and death can occur outside of this narrow pH range pH < 7.35 is acidotic pH > 7.45 is alkalotic Body acid acid acid Buffer Buffer Phormal Buffer weak acid Buffer systems Buffer solutions are aqueous solutions that are made up of a mixture of a weak acid and its conjugate base The pH of buffer solutions don’t change very much when small amounts of strong acid or base is added to the aqueous solution Buffers are in dynamic equilibrium and conjugate base weakacid HA weakbase conjugate Doesntfully Fluorine Acetate products reactors Getbennemrade of Dynamic equilibrium rate of formation aÉEmade re moves forward depending on time Adding more reactants will push the system to create more products Adding more products will push the system to crease more reactants Removing products will push the system to create more products (resulting in a decrease of reactants) Removing reactants will push system to create more reactants (resulting in a decrease of products) or backwards concentration Buffer systems Buffer Systems in the body: ECF Carbonic acid – bicarbonate Proteins Phosphates ICF Carbonic acid – bicarbonate Hemoglobin Proteins Phosphates Carbonic acid – bicarbonate buffer CO2 is a product of cellular respiration CO2 combines with H2O to create carbonic acid (H2CO3)* H2CO3 dissociates into bicarbonate (HCO3-) and a hydrogen ion (H+) *Carbonic anhydrase Carbonic acid – bicarbonate buffer CO2 of by exhale pH < 7.35 is acidotic Acidemia is generally caused by - increase rid of get carbon dinohe An increase in hydrogen ions Loss of bicarbonate ions Less HCO3- means the entire equation shifts to the right in order to maintain equilibrium Result is that there is more free hydrogen ion in circulation An increase in CO2 Carbonic acid – bicarbonate buffer pH >7.45 is alkalotic Alkalemia is generally caused by Loss of hydrogen ions An excess of bicarbonate ions Increasing the [bicarbonate ion] means that more of it will bind to the available hydrogen forming carbonic acid (and, consequently, more CO2 + H2O) Result is that there is less free hydrogen ion in circulation A decrease in CO2 - CO2(gas) H+(excreted into urine) HCO3-(reabsorbed into blood) Net excretion of H+ creates new HCO3- Fast response - minutes Slow response - days Acid-base disorders Hypoventilation can lead to increase in retained CO2 and a subsequent increase in acid Metabolic acidosis Too much metabolic acid being made / ingestion of acid Difficulty of kidneys to excrete hydrogen ions Result is a decrease in plasma bicarbonate which causes an increase in acid - Respiratory acidosis Acid-base disorders Hyperventilation can lead to too much CO2 being exhaled and a subsequent decrease in acid Metabolic alkalosis Excess loss of acid through GI or through kidneys Ingestion of alkali Result is an increase in plasma bicarbonate retention which causes a decrease in acid - Respiratory alkalosis Other Buffers Hemoglobin Hgb can reversibly bind either H+ or O2 In tissue capillaries, O2 is low and CO2 is high (so, CO2 can diffuse into cells where it combines with water to make carbonic acid and subsequently increases H+) Deoxygenated Hgb can bind the H+ Bicarb can be moved out of the cell in exchange for a chloride anion This process is reversed in lung capillaries Protein Proteins carry a negative charge Can combine with hydrogen ion TL; DR: buffer systems Enzymatic reactions in the body work within a narrow pH Buffer systems regulate the pH, which is necessary as we produce acids and bases during metabolism (and can ingest them) Buffers are made up of a weak acid and its conjugate base They can absorb small amounts of strong acid or base without much of a corresponding change in the pH The bicarbonate buffer is the most important system CO2, which is a component of the bicarbonate buffer, can be removed from the lungs to aid in adjustment of blood pH The kidney controls how much bicarbonate is reabsorbed and/or produced and thus can aid in adjustment of blood pH