PHYSIO_LC3_TRANSPORT OF SUBSTANCES THROUGH CELL MEMBRANES.pdf

COURSE OUTLINE B. CELL MEMBRANE TRANSPORT I. CELL MEMBRANE In diffusion, carrier proteins and channel proteins A. Composition...

COURSE OUTLINE B. CELL MEMBRANE TRANSPORT I. CELL MEMBRANE In diffusion, carrier proteins and channel proteins A. Composition are present. These carrier proteins are responsible B. Cell Membrane Transport for both passive and active transport. Channel B. 1. Diffusion Vs Active proteins are only responsible for diffusion. Transport Channel proteins: have a hollow space B. 2. Lipid Solubility and water space; free-flowing B. 3. Facilitated Diffusion Carrier proteins: protein as a whole on its B. 4. Simple Diffusion Vs. own Facilitated Diffusion B. 5. Osmosis B. 6. Osmolality B. 7. Osmolarity II. I. CELL MEMBRANE Figure 2. Transport pathway through the cell membrane and the basic mechanics of transport. A. DIFFUSION – movement of substances molecule by molecule, either through intermolecular spaces in the membrane or in combination with a carrier protein – normal kinetic motion of matter – less effort Two subtypes of diffusion: a. AQUAPORINS Figure 1. Structure of the cell membrane – protein “pores” of the cell membrane – selectively permit rapid passage of water CELL MEMBRANE – AKA “plasma membrane” through the membrane – consists almost entirely of a phospholipid bilayer – other lipid-insoluble molecules can pass with large number of proteins through the protein pore channels in the same – 7.5 to 10 nm thick way as water molecules if they are water soluble and small enough Phospholipid Bilayer: Hydrophilic head b. PROTEIN CHANNELS Hydrophobic tail Characteristics: – often selectively permeable to certain A. COMPOSITION substances – regulated by electrical signals 55% Proteins (VOLTAGE-GATED CHANNELS) or chemicals 25% Phospholipids that bind to the channel proteins 13% Cholesterol (LIGAND-GATED CHANNELS) 4% other lipids 3% Carbohydrates POTASSIUM CHANNEL - permits passage of potassium ions across the cell membrane about 1000 times more readily than they permit passage of sodium ions. – Tetrameric structure consisting of four identical protein subunits surrounding a central pore. BATCH 2028 1A 1 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 suddenly and allow sodium to pass inward through the sodium pores. – potassium gates are on the intracellular ends of the potassium channels – they open when the inside of the cell membrane becomes positively charged CHEMICAL (LIGAND) GATING – chemical substance (a ligand) binds with the protein = conformational or chemical bonding change in the protein molecule that opens or closes the gate E.g. Acetylcholine channel SODIUM CHANNEL – 0.3 to 0.5 nanometer in diameter – inner surfaces of this channel are lined with amino acids that are strongly negatively charged. – can pull small, dehydrated sodium ions into these channels Open State vs Closed State of Gated Channels - At one voltage potential, the sodium channel may remain closed all the time or almost all the time - Another voltage level, it may remain as open whether all or most of the time - In-between voltages, the gates B. ACTIVE TRANSPORT - requires effort - with a carrier protein - move against an energy gradient - from a low-concentration state to a high-concentration state Figure 3. Transport of sodium and potassium ions - requires an additional source of energy through protein channels. Also shown are conformational changes in the protein molecules to DIFFUSION OF LIPID-SOLUBLE SUBSTANCES open or close the “gates” guarding the channels. THROUGH THE LIPID BILAYER The rate of diffusion of each of these TYPES OF GATES: substances through the membrane is VOLTAGE GATING directly proportional to its lipid solubility. – negative charge on the inside of the cell membrane = sodium gates to remain FACILITATED DIFFUSION tightly closed Also called carrier-mediated diffusion – inside of the membrane loses its The carrier facilitates diffusion of the negative charge = gates would open substance to the other side BATCH 2028 1A 2 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 SIMPLE DIFFUSION VS. FACILITATED DIFFUSION The rate of diffusion into the cell is proportional to the concentration on the outside minus the concentration on the inside, or: Net Diffusion ∝ (Co - Ci) In which Co is concentration outside and Although the rate of simple diffusion through an Ci is concentration inside. open channel increases proportionately with the concentration of the diffusing substance, in 2. Effect of membrane electrical potential facilitated diffusion the rate of diffusion approaches on diffusion of ions– the “Nernst a maximum, called Vmax, as the concentration of Potential” the diffusing substance increases. What is it that limits the rate of facilitated diffusion? Because the binding force of the receptor is weak, the thermal motion of the attached molecule causes it to break away and be released on the opposite side of the membrane. The rate at which molecules can be transported by this mechanism can never be greater than the rate at which the The positive charge attracts the negative carrier protein molecule can undergo ions, whereas the negative charge change back and forth between its two repels them. states. NERNST EQUATION - At normal body temperature (37oC), the electrical difference that will balance a given concentration difference of univalent ions–such as Na+ ions– can be determined from the following formula EMF (in millivolts)= ±61log C1/C2 EMF: electromotive force (voltage) between side 1 and side 2 of the membrane, C1 is the concentration on side 1, and C2 is the concentration on Figure 6. Postulated mechanism for facilitated side 2. diffusion. 3. Effect of a pressure difference across the membrane FACTORS THAT AFFECT NET RATE OF DIFFUSION 1. Net Diffusion Rate is proportional to the concentration difference across a membrane BATCH 2028 1A 3 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 The result is that increased amounts of energy are available to cause net movement of molecules from the high-pressure side toward the low-pressure side. High pressure side to low pressure side. Concentration difference of water can develop across a membrane OSMOSIS ACROSS SELECTIVELY PERMEABLE MEMBRANE I. Osmosis Concentration difference for water can develop across a membrane Process of net movement of water does occur across the cell membrane → causing the cell to either swell or shrink, depending on the direction of the water Figure 11. Demonstration of osmotic pressure movement caused by osmosis at a semipermeable membrane. IV. Importance of molar concentration in determining osmotic pressure Each particle in a solution, regardless of its mass, exerts, on average, the same amount of pressure against the membrane. large particles: slower velocity small particles: higher velocity The factor that determines the osmotic pressure of a solution is the concentration of the solution in terms of the number of particles (which is the same as its molar concentration if it is a non dissociated Figure 10. Osmosis at a cell membrane when a molecule), not in terms of mass of the sodium chloride solution is placed on one side of solute. the membrane and water is placed on the other side. OSMOLALITY Osmole – is the unit to express the II. Net Diffusion of Water concentration of a solution in terms of numbers of particles Water: most abundant substance that One osmole = 1 gram molecular weight of diffuses through the cell membrane osmotically active solute E.g. 1 osmole of solute dissolved in each III. Osmotic Pressure: amount of pressure kilogram of water = osmolality of 1 osmole per kg required to stop osmosis Solution that has 1/1000 osmole dissolved per kilogram has an osmolality of 1 A pressure difference develops between milliosmole per kilogram two sides of the membrane great enough The normal osmolality of the extracellular to oppose the osmotic effect and intracellular fluids is about 300 If pressure were applied to the sodium milliosmoles per kilogram of water. chloride solution, osmosis of water into this Normal osmolality of the ECF and ICF is solution would be slowed, stopped, or about 300 milliosmoles per kilogram of even reversed. water isotonic solution: same concentration of solute to the blood Hypotonic solution: lower concentration Relation of osmolality to osmotic pressure of solute in the blood At normal body temperature, a Hypertonic solution: higher concentration concentration of 1 osmole per liter will of solute in the blood. cause 19,300 mmHg osmotic pressure in the solution 1 milliosmole per liter concentration is equivalent to 19.3 mmHg osmotic pressure. BATCH 2028 1A 4  PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 19.3 mmHg x 300 milliosmolar concentration = 5790 mmHg The measured osmotic pressure of the body fluids averages only about 5500 mm Hg On average, the actual osmotic pressure of the body fluids is about 0.93 times the calculated value. OSMOLARITY Is the osmolar concentration expressed as osmoles per liter of solution rather than osmoles per kilogram of water. Measuring osmolarity is the usual practice in almost all physiological studies. Figure 11. The postulated mechanism of the ACTIVE TRANSPORT sodium-potassium channel pump. ADP, adenosine diphosphate, ATP, adenosine The process when a cell membrane moves triphosphate:Pi, phosphate ion. molecules or ions “uphill” against a concentration gradient (or “uphill” against an electrical or ○ Electrogenic Nature pressure gradient) - A net of one positive charge is moved from the interior of the cell to the exterior Substances that are actively transported through of each cycle of the pump at least some cell membranes include sodium, One positive charge goes outside potassium, calcium, iron, hydrogen, chloride, iodide, every pump. This means that the and urate ions, several different sugars, and most of inside of the membrane is more the amino acids. negative than the outside. It maintains the more negative PRIMARY ACTIVE TRANSPORT and less positive inside the The energy is derived directly from breakdown membrane. of adenosine triphosphate (ATP) or some other Positive pole →OUTSIDE high-energy phosphate compound Negative pole →INSIDE SODIUM POTASSIUM PUMP ○ This electrical potential is a basic ○ pump sodium outside and potassium requirement in nerve and muscle fibers inside for transmitting nerve and muscle ○ A transport process that pumps sodium signals. ions outward through the cell membrane CALCIUM PUMP of all cells and at the same time pumps ○ Primary active transport of calcium ions potassium ○ Calcium ions concentration in the ○ Responsible for maintaining the sodium intracellular cytosol of virtually all cells in outside and the potassium inside the cell the body is about 10,000 times less than ○ Requires energy because it is against that in the extracellular fluid energy or concentration gradient, ○ The carrier protein is a complex of two TWO PRIMARY ACTIVE TRANSPORT separate globular proteins: CALCIUM PUMPS ○ Alpha Subunit: the functional unit. 1. CELL MEMBRANE - pumps Larger calcium to the outside of the cell 3 binding unit inside for Na+ and 2. INTRACELLULAR VESICULAR 2 binding unit outside for K ORGANELLES OF THE CELL – The inside portion of this protein such as the sarcoplasmic reticulum near the sodium binding sites has of muscle cells and the adenosine triphosphate (ATPase) mitochondria in all cells activity. One of the most important functions is controlling PRIMARY ACTIVE TRANSPORT OF cell volume. Without the function HYDROGEN IONS of this pump, most cells of the body would swell until they burst. 1. PARIETAL CELLS – in the gastric ○ Beta subunit: the nonfunctional subunit glands of the stomach Smaller 2. INTERCALATED CELLS - in the No function. late distal tubules and cortical ○ Maintains cell volume - where sodium collecting ducts of the kidneys goes, water follows ○ Failure of Sodium potassium pump→Cell I. PARIETAL CELLS Lysis - Have the most potent primary active BATCH 2028 1A 5 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 mechanism for transporting hydrogen ions diabetes, it removes the excess glucose so of any part of the body that it will not be reabsorbed - At the secretory ends of the gastric gland GluTs (Glucose Transporters - found parietal cells, the hydrogen ion mainly in intestines and kidneys. concentration is increased as much as a GLUT1 - intestines million-fold and then is released into the GLUT2 - kidneys stomach along with chloride ions to form GLUT3 - blood, brain hydrochloric acid. GLUT4 - muscle and adipose tissue GLUT5 - fructose transport in intestine II. INTERCALATED CELLS - Found in the late distal tubules and cortical Counter transport collecting ducts of the kidney ○ Sodium Ion binds to the carrier protein - Transport hydrogen ions by primary active where it projects to the exterior surface of transport the membrane, while the substance to the - Hydrogen ions are secreted from the blood con-transported protein binds to the into the urine for the purpose of eliminating interior projection of the carrier protein. excess hydrogen ions from the body fluids. - The hydrogen ions can be secreted into ○ Sodium ion binds to the carrier protein the urine against a concentration gradient where it projects to the exterior surface of of about 900-fold. the membrane, while the substance to the - Some cells, such as those lining the renal counter-transported binds to the interior tubules and many glandular cells, expend projection of the carrier protein. as much as 90 percent of their energy ○ Once both have become bound, a conformational change occurs, and energy SECONDARY ACTIVE TRANSPORT released by the action of the sodium ion The energy is derived secondarily from moving to the interior causes the other energy that has been stored in the form of substance to move to the exterior. ionic concentration differences of ○ SODIUM-CALCIUM COUNTER secondary molecular or ionic substances TRANSPORT between the two sides of a cell membrane, Occurs through all or almost all created originally by primary active cell membranes transport. In short, it uses energy derived Sodium ions moving to the from primary active transport. interior and calcium ions to the Borrowing energy from primary active exterior transport Both are bound to the same transport protein in a 2 forms: CO-TRANSPORT and COUNTER counter-transport mode TRANSPORT Addition to primary active Co-transport transport of calcium that occurs in ○ A coupling mechanism is required. some cells ○ Carrier in this instance serves as an ○ SODIUM-HYDROGEN COUNTER attachment point for both the sodium ion TRANSPORT and the substance to be co-transported. Especially important example is in ○ Once they are both attached, the energy the proximal tubules of the gradient of the sodium ion causes both the kidneys sodium ion ion and the other substance to Transport hydrogen ions in the be transported together to the interior of gastrointestinal and gastric cells. the cell. Maintains the acidity of urine ○ Example of co-transport: sodium and Every exchange of sodium gets glucose. The sodium-glucose two extra hydrogen ions to co-transporters are an important maintain the normal blood pH. mechanism in transporting glucose across renal and intestinal epithelial cells. ACTIVE TRANSPORT THROUGH CELLULAR ○ SODIUM-GLUCOSE CO-TRANSPORT: SHEETS found mainly in the intestines. Cells need to coordinate with other cells It allows the absorption of glucose. and an example of this is the active transport It is an important mechanism in through cellular sheets. transporting glucose across renal and intestinal epithelial cells because they are Active transport occurs through the: targeted by medication. 1. Intestinal epithelium It occurs especially through the epithelial 2. Epithelium of the renal tubules cells of the intestinal tract and the renal 3. Epithelium of all exocrine glands tubules of the kidneys to promote 4. Epithelium of the gallbladder absorption of these substances into the 5. Membrane of the choroid plexus the brain, blood along with other membranes SGLT (Sodium-glucose Transporters) - in BATCH 2028 1A 6 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 Depolarization Stage - The membrane suddenly becomes permeable to sodium ions, allowing rapid diffusion of positively charged sodium ions to the inferior of the axon. The normal polarized state of -70 millivolts is immediately neutralized by the inflowing, positively charged sodium ions, with the potential rising rapidly in the positive direction. Figure 12. The basic mechanism of active transport across a layer The basic mechanism for transport of a substance through a cellular sheet is: 1. Active transport through the cell membrane on one side of the transporting cells in the sheet,and Figure 14. During this activated state, sodium ions then can pour inward through the channel, increasing the 2. Either simple diffusion or sodium permeability of the membrane. facilitated diffusion through the membrane on the opposite side Repolarization Stage - within a few 10,000ths of the cell. of a second after the membrane becomes highly permeable to sodium ions, the sodium channels begin to close. Rapid diffusion of ENERGETICS OF PRIMARY ACTIVE potassium ions to the exterior re-established TRANSPORT the normal negative resting membrane potential. In terms of calories, the amount of energy required to concentrate 1 osmole of a substance 10-fold is about 1400 calories, whereas to concentrate it 100-fold, 2800 calories are required STAGES OF THE ACTION POTENTIAL Resting Stage - The membrane is said to be “polarized” during this stage because of the -70 millivolts negative membrane potential that is present. Figure 15. The decrease in sodium entry to the cell and the simultaneous increase in potassium exit from the cell combine to speed the repolarization process, leading to full recovery of the resting membrane potential VOLTAGE-GATED SODIUM AND POTASSIUM CHANNELS These two voltage-gated channels are in addition to Figure 13. The upper left of the figure depicts the the Na+ - K+ pump and the K+ leak channels. state of these two gates in the normal resting membrane. In this state, the activation gate is VOLTAGE-GATED SODIUM CHANNEL - the closed, which prevents any entry of sodium ions to necessary factor in causing both the interior of the fiber through these sodium depolarization and repolarization of the nerve channels. During the resting state, the gate of the membrane during the action potential. It also potassium channel (lower left) is closed and maintains the cell volume because where potassium ions are prevented from passing through sodium goes, water follows. If you put sodium this channel to the exterior inside, the water will follow inside of the cell. On the other hand, if you put sodium outside BATCH 2028 1A 7 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 of the cell, the water will also go outside of the showing successive activation and inactivation of cell. the sodium channels and delayed activation of the potassium channels when the membrane potential -This channel has two gates: activation gate is changed from the normal resting negative value (near the outside) and inactivation gate (near to a positive value. the inside) ○ ACTIVATION: When the membrane potential CONDUCTION OF ACTION POTENTIAL becomes less negative than during the resting Propagated Action Potential state. Action potential arrives at successive points - rising from -90 millivolts toward zero, traveling along the axon, its shape and size finally reaches a voltage that causes a remain constant because it regenerates sudden conformational change in the itself as it is conducted along the fiber. activation gate. An excitable membrane has no single direction of propagation. ○ INACTIVATION: The same increase in The action potential travels in all directions voltage that opens the activation gate also away from the stimulus– even along all closes the inactivation gate. The inactivation branches of a nerve fiber– until the entire gate, however, closes a few 10,000ths of a membrane has become polarized. second after the activation gate opens. - Conformational change that flips the ACTION POTENTIAL CONDUCTION VELOCITY inactivation gate to the closed state is a IS CORRELATED WITH AXON DIAMETER slower process than the conformational change that opens the activation gate. The speed of conduction in a nerve fiber is - the inactivation gate will not reopen until determined by the electrical properties of the the membrane potential returns to or cytoplasm and the plasma membrane that near the original resting membrane surrounds the fiber, and by its geometry potential level. - The action potential is conducted faster VOLTAGE-GATED POTASSIUM along fibers with large diameter CHANNEL - plays an important role in Continuous conduction happens in increasing the rapid repolarization of the voltage-gated Na+ channels that are membrane. slower. ○ ACTIVATION: When the membrane potential rises from −90 millivolts toward ROLES OF OTHER IONS DURING THE ACTION zero, this voltage change causes a POTENTIAL conformational opening of the gate and allows increased potassium diffusion 1. Impermeant Negatively Charged Ions (Anions) outward through the channel. Inside the Nerve Axon. Anions of protein molecules and of many - Slight delay in opening of the potassium organic phosphate compounds and sulfate channels = they open just at the same compounds time that the sodium channels are Responsible for the negative charge inside beginning to close because of the fiber when there is a net deficit of inactivation. positively charged potassium ions. 2. Calcium Ions. Membranes of almost all cells of the body have a calcium pump similar to the sodium pump. Contribute to the depolarizing phase on the action potential in some cells. The gating of calcium channels, however, is relatively slow, requiring 10 to 20 times as long for activation as for the sodium channels. 3. Increased Permeability of the Sodium Channels When There Is a Deficit of Calcium Ions. These ions appear to bind to the exterior surfaces of the sodium channel protein. The positive charges of these calcium ions, in turn, alter the electrical state of the Figure 12. Characteristics of the voltage-gated sodium channel protein, thus altering the sodium (top) and potassium (bottom) channels, voltage level required to open the sodium BATCH 2028 1A 8 PHYSIOLOGY LC 3: MEMBRANE PHYSIOLOGY Dr. UJANO, S. A.. 09/01/2024 gate. INHIBITION OF EXCITABILITY - STABILIZERS AND LOCAL ANESTHETICS 1. Membrane-Stabilizing Factors Can Decrease Excitability. E.g. a high extracellular fluid calcium ion concentration decreases membrane permeability to sodium ions and simultaneously reduces excitability. Therefore, calcium ions are said to be what is called a stabilizer. 2. Local Anesthetics. Most of these agents act directly on the activation gates of the sodium channels, making it much more difficult for these gates to open and thereby reducing membrane excitability. When excitability has been reduced so low that the ratio of action potential strength to excitability threshold (called the safety factor) is reduced below 1.0, nerve impulses fail to pass along the anesthetized nerves. Reference(s): John E. Hall, P. (2016). Guyton and Hall Textbook of Medical Physiology 13th edition. Philadelphia: Elsevier Saunders. BATCH 2028 1A 9