Membrane Transport

  • Created by: LBCW0502
  • Created on: 13-04-18 11:29
Describe features of biological membranes
Essential cellular components, physically separate cells from its environment and separates compartments within cells (cell organelles)
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Describe features of a plasma membrane
Defines the external boundaries and separates cells from its environment. Holds cell constituents together. Prevents materials from entering (serves as semi-porous barrier to external environment)
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Describe features of the fluid mosaic model
Phospholipid bilayer with glycoproteins. Phospholipid contains polar head and non-polar tail. Proteins arranged relating to solubility
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What is selective permeability?
Permeable to specific molecules required by cell processes (e.g. nutrients). Non-permeable to unwanted material. Lipid bilayer is a hydrophobic barrier
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Which type of molecules display good permeability?
Hydrophobic molecules and small uncharged molecules
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Which ions have very low permeability?
Small ions e.g. Na+, K+, Cl- (unable to diffuse across membranes)
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Describe features of passive diffusion
Passage through lipid portion of cell membrane, doesn't involve transport proteins, doesn't use cellular energy
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Describe features of specialised mechanisms
Involves carriers (transport proteins), carrier mediated transport, may or may not use cellular energy
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What is the difference between active and passive transport?
Passive transport doesn't require energy (driven by concentration/electrical gradients). Active transport requires energy (works against concentration/electrical gradient)
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Do molecules need to be in solution for transport?
Yes (either in extracellular fluid or intracellular fluid) - exception is the fluid phase in pinocytosis (not an important mechanism of drug transport)
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Describe features of simple diffusion
Solute moves through permeable membrane from region of high concentration to region of low concentration (equilibrium). Spontaneous (increase in S, decrease in delta G). No requirement for energy. Rate depends on conc. gradient
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Simple (passive diffusion) applies to which molecules?
Small, lipid soluble molecules e.g. ethanol. Non-polar gases e.g. O2, CO2. Hydrophobic molecules e.g. steroid hormones, lipid soluble vitamins/drugs
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Why are large polar molecules unable to cross membranes via passive diffusion?
They are repelled by the hydrophobic interior of lipid bilayers
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What must a drug have in order to be able to pass through the cell membrane?
An appropriate combination of water and lipid solubility
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Which processes are involved in passive diffusion?
1. Break bonds (e.g. H bonds) with aqueous medium. 2. Enter lipid region. 3. Cross lipid region via diffusion. 4. Leave membrane at the other side. 5. Reform any bonds with aqueous medium (steps 1,2,4,5 are partitioning steps - solubility)
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What are the energy changes associated with membrane transport?
A hydrophilic/charged solute must give up interactions with water molecules in hydration shell. Diffuse through lipid in which it is poorly soluble. Transmembrane passage is an high-energy state (need to overcome Ea)
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The rate of diffusion depends on which factors?
Diffusion coefficient (D) - size of molecule and nature of membrane (smaller molecule/higher rate of diffusion). Concentration gradient, thickness of membrane, SA
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Describe features of Fick's First Law of Diffusion
Takes into account SA, D, conc. gradient, concentration of molecule and thickness. Conc. gradient influenced by partition coefficient from drug molecules wrt membrane. Equation only applies to uncharged molecules
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What are sink conditions?
Drug is removed by bloodstream as soon as it crosses the membrane (C2 = 0). Concentration of drug at site of absorption is the main variable affecting rate of diffusion
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Molecules move under the influence of what type of motion?
Brownian motion (flux - direction of concentration gradient)
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What does the pH partition hypothesis explain?
Passage of drugs across GI tract after oral administration. Hypothesis only applies to molecules crossing via transcellular route (through cells) by passive diffusion
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Explain the 1st part of the hypothesis
pH - only unionised form of molecule crosses membranes due to higher lipid solubility (ionisable compounds - dependent on pH of environment)
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Explain the 2nd part of the hypothesis
Partitioning - molecules cross membranes at a rate dependent on their lipid solubility (Log P - partition coefficient)
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Weak acidic drugs are absorbed where?
In the stomach (pH 1-3 for drugs with pKa ~3)
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Weak basic drugs are absorbed where?
In the SI (pH 5-8 for drugs with pKa ~8)
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Why does the pH-partition hypothesis fail?
Difference in SA of stomach and SI. Most drugs are absorbed in the SI
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How do you calculate log P?
Concentration in organic phase / concentration in aqueous phase (>>1 more lipophilic,
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A drug should have a log P value within which range in order to cross the membrane?
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Why does the hypothesis fail at high log P values?
Solubility limited diffusion across membrane, unstirred water layer, presence of bile, SA of SI
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Why does the hypothesis fail at low log P values?
Paracellular route
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Which mechanisms are used to transport macromolecules (e.g. biopolymers, large molecular mass)?
Exocytosis and endocytosis
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What is endocytosis?
Membrane invagination to form a vesicle moving the enclosed materials inside the cell. Also regulates amount of cell surface receptors
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What is phagocytosis?
Cell engulfs objects - occurs in specialised cells - cell eating
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What is pinocytosis?
Cell engulfs extracellular fluid in which molecules are present. Material enters cell inside a vesicle but doesn't mix with cytoplasm - cell drinking
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What is receptor-mediated endocytosis?
Allows cells to take up specific macromolecules (ligands)
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Endocytosis and transcytosis are important for what?
Pharmaceutical science e.g. drug delivery to cells by nanoparticles
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Membrane permeability of a molecule depends on what?
Small molecular size, low polarity, no charge, medium solubility in oil, medium solubility in water (permeability increases with temperature)
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Describe components in a typical animal cell
SER, RER, nucleus, nucleolus, mitochondria, centrioles, plasma membrane, lysosomes, vacuole, Golgi apparatus
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What are integral proteins?
They facilitate transport of molecules which cannot diffuse across lipid bilayers - they are called transporters, permeases, translocases or carrier proteins
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What are the types of transport?
Simple diffusion, passive transport, active transport (primary/secondary), ion channels
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Describe features of facilitated transport
Similar to an enzyme catalysed reaction. The amount of energy required to transport a substance via a membrane protein is considerably less than would be required without it
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Describe features for kinetics of facilitated transport
Michaelis-Menten kinetics. Proteins that bring about facilitated diffusion are not enzymes (substances are not chemically altered and process of reversible)
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What are ionophores?
Ion bearers - selective bind ions, displacing hydration shell to make ions lipid soluble and facilitate movement across membranes. They can act as uncouplers of processes which rely upon ion gradients e.g. valinomycin (peptide antibiotic) binds to K+
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Describe features of 2,4-dinitrophenol (DNP)
Weak acids (pKa 4.1), able to diffuse across inner mitochondrial membrane in protonated form (release proton into matrix). DNP couples with electron transport from ATP production
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What are the three types of transport (active)?
Uniport (one substrate in), symport (two substrates in) and antiport (one substrate in, one substrate out). Symport and antiport are cotransports
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Describe features of the alternating access model
Carrier proteins cycle between conformations, substrate binding site is accessible on one/other side of membrane. Intermediate conformation in which bound substate is inaccessible to either aqueous environment. No open channel through membrane
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Describe features of the glucose transporter (uniport)
Glucose transport to the brain and muscle cells (GLUT). Binding to glucose induces conformational change (opens channel to opposite side). Weak binding of glucoses causes it to break away from carrier/enter cell - use of amino acids (reversible)
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Describe drug transport by uniports
L-dopa transported across membranes by L-phenylalanine transporter protein. Across BBB, L-dopa may be decarboxylated to form DA
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Describe features of Cl-/HCO3- co-transporter (antiport)
CO2 taken in by erythrocytes, reacts with water to form carbonic acid, dissociates to form H+ and HCO3-. HCO3- exchanged with Cl-
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Describe features of Na+ amino acids co-transporter (symport)
Carrier protein from intestinal lumen of enterocyte cytoplasm. Energy provided when Na+ is co-transported down a concentration gradient (secondary transporter). Conformational change, transport occurs only when both substrates are bound to carrier
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Describe features of 3Na+ amino acids co-transporter (GLAST)
Increased [Na+] increases affinity for amino acids (aspartate) substrate). Helical hairpin structure
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Describe features of drug transport by symporters (1)
PEPT1 (di/tripeptide/H+ symport), transports non-peptide drug molecules from gut (increase F), e.g. beta-lactam antibiotics, ACE inhibitors (to reduce b.p.) and prodrugs. Drug molecules transported out of cell via transporters to peptides/amino acids
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Describe features of drug transport by symporters (2)
Drug mimics region of peptide structure. Certain drugs interact with peptide binding site on transporter. The greater the structural similarity between the drug and peptide, the greater the affinity for the transporter
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Describe features of drug transport by symporters (3)
Drugs with poor F may be chemically modified for specific transporters. Antiviral drug acylovir may be esterified with amino acid valine to frm prodrug valacyclovir (transport from gut into enterocytes by PEPT1, hydrolysed in cell to active acyclovir
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What is facilitated transport?
Movement down concentration gradient
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What is active transport?
Movement against concentration gradient. Requires energy (from hydrolysis of ATP)
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Give examples of ATP-powered pumps
P-ATPase, V-ATPase, F-ATPase and ABC transporter (ATP binding cassette)
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Describe features of Na+, K+ ATPase (P-class)
Phosphorylation of transporters by ATP (sodium ions in, potassium ions out). Maintains concentration gradients. Resting potential of -50 to -70 mV. ATP hydrolysis is exergonic. Movement of Na/K is endergonic
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Describe features of coupled transport processes
In gut epithelial cells, carrier proteins are distributed asymmetrically in the plasma membrane. Glucose/Na+ co-transporters are situated on apical membrane. Na+ pumps and glucose uniports are on basolateral membrane
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Describe the coupled transport process for glucose
Glucose enters cell via apical symport with energy provided by influx of Na+. SGLT1 intestinal Na+ coupled GLUT1. Glucose leaves cell via specific basolateral GLUT2 - facilitated transport
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Describe features of lysosomal proton pump (V-class)
Low pH of lysosome creates optimum conditions for acid hydrolase enzymes. Autolysis of cell organelles/hydrolysis of macromolecules/bacterial cells entering cell/endocytosis. Hydrolysis of ATP coupled with proton pumps - cytoplasm/lysosome
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Describe features of ATP synthase (F-ATPase)
Mitochondrial super engine. Flow of protons across membrane down concentration gradient (accompanied by ATP synthesis from ADP and Pi, the reversal of ATP hydrolysis)
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Describe features of ABC transporters
4 domains, 2 transmembrane domains and 2 nucleotide binding domains. Human ABC transporters found in ER, lysosome and mitochondria as well as plasma membrane
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ABC transporters participate in what?
Cholesterol and lipid transport, multidrug resistance, antigen presentation, mitochondrial Fe homeostasis and ATP dependent regulation of ion channels (cystic fibrosis, diabetes, hypercholesterolaemia)
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Describe features of cystic fibrosis transmembrane conductance regulator
ABC Cl- transporter in epithelial cells of e.g. lung/GI tract. Maintain electrolyte balance e.g. lung mucous. Reduced Cl- leads to water uptake and thick mucous, Mutations lead to disruption. Thick mucous - chronic infection
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Describe features of permeability glycoprotein (P-gp) - multidrug resistance protein 1, MDR1
Broad range of substrates, hydrophobic compounds. Highly expressed in gut, liver kidney, brain and placenta, restricting F of therapeutic drugs. Over-expressed by neoplastic cells reducing efficacy of cytotoxins such as doxorubicin
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Describe features of ion channels
Ion-selective (narrow and highly selective pores). Voltage, ligand or mechanically-gated stimulation. Ion transport is down gradient. Very fast rate of 10^7-10^8 ions/second (synapse)
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Describe features of action potential
Nerve impulses propagated by entry of Na+ into neurones after opening of gated Na+ channels in membrane. K+ channels open later to release K+ from cell. Resting potential later restored by action of Na+ pump
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