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1

 

Discuss the principles of solute movement across biological membranes

  • Hydrophobic molecules can pass through membranes.
  • Small uncharged polar molecules can pass through membranes.
  • Large uncharged polar molecules need a specific protein transporter as they are too big to diffuse across.
  • Ions are charged and so thermodynamics will not allow diffusion
  • Non-polar molcules are able to enter and diffuse across the hydrophobic domain of lipid bilayers.

2

Cmpare permeability coefficients especially regarding water

  • movement of water across membranes by OSMOSIS
  • Permeability coefficients for most ions and hydrophilic molecules in lipid bilayers are very low (<10-10cm/s)  but membranes are extremely permeable to water (5x10-3cm/s)
  • Water will diffuse passively across lipid bilayer UP the concentration gradient of a soution (the osmotic gradient)
  • in some cells e.g. proximal kidney tubules, the movement of water may be facilitated by specific water channels (aquaporins).
  • Permeability may be controlled - switched on and off depending on the function of the membrane.
  • In the human erythrocyte membrane, Band 3 Protein specifically transports Cl- (hence increased permeability) and the membrane also has a glucose transporter (main substrate for glycolysis so very important).

3

Why do membranes act as permeability barriers to all charged and hydrophilic molcule?

The large free energy change that would be required for a small hydrophilic molecule or ion to traverse the hydrophobic core of the lipid bilayer makes the transverse movement of hydrophilic molecules across an intact biological membrane a rare event

4

What do specific membrane transport systems do?

They mediate and regulate the movment of ions and hydrophilic molecules across a membrane. The processes have important roles:

  • Maintenance of intracellular pH
  • Maintenance of cell volume
  • Regulation of cell volume
  • Concentration of metabolic fuels and building blocks
  • Extrusion of waste products of metabolism and toxic substnces
  • The generation of ionic gradients necessary for the electrical excitability of nerve and muscle.

5

Describe Passive Diffusion

  • Dependent on permeability and concentration gradient.
  • Rate of passive transport increases linearly with increasing concentration gradient (excluding proteins).

6

Describe Facilitated Diffusion

  • Specific proteins in the bilayer can increase the permeability for a polar substance e.g. Band 3 Protein increases the permeability of  phosphatidylserine bilayer for Cl-. . Band 3 doesn't just form a Clselective pore but carries out a specific exchange of Cl- for HCO3- which is essetial to the function of the erythrocyte.
  • Models for facilitated transport include protein pores (ion selectve channels) and carrier moleules (gated pores - ping pong).
  • Protein flip flop and rotation are thermodynmically unfavourable.
  • Facilitated transport is saturable as each carrier can interact with only one or a few ions or molecules at any moment and a finite number of transporters are present in the membrane. As the concentration gradient increases, a maximum rate of transport will be measured when all the transporters are busy.
  • Similar to enzymes, the equilibrium point for the transported species is not altered by facilitated transport.

7

Explain how some protein pores/protein channels may be gated?

  • Ligand-gated ion channels open or close in response to a ligand binding to a receptor site: normally channels. E.g. ACh binding opens specific channel (nACHr) which allws influx  of Na+. Another E.g. is ATP binding to potassium selective channels. They are normally open but ATP binding closes ATP-sensitive K+ channels.
  • Voltaged-gated ion channels on and clse in response to the potential difference across the membrane. Depolarisaion repels positively charged membrane segment upwards, driving a conformational change and allowing influx of Na+
  • Gap Junction (connexin) is closed when cellular calcium concentration rises above 10 micromoles - when the cell becomes acidic.

8

What determin whether the transport of an ion or molecule is Active or Passive?

  • Whether transport of an ion or molecule can occur spontaneously (passive) or requires energy (active) is deterined by the free energy change of the transported species
  • The free energy change is determined by the concentration gradient for thetransported species and by the electrical potential across the membrane bilayer when the transported species is charged.

9

Describe Active Transport

  • Active transport allows the transport of ions of molecules against an UNFAVOURABLE CHEMICAL CONCENTRATION AND/OR ELECTRICAL GRADIENT.
  • The movement of the transported ion or molecule must be coupled to a thermodynamically favourable reaction.
  • The free energy to drive active transport can come either directly or indirectly from the hydrolysis of ATP, electron transport or light.
  • Some cells may spend up to 30-50% of their ATP on active transport

10

Describe a Cotransporter and give examples

  • These transporter transport more than one type of ion or molecule per reaction cycle e.g.
  • Na+-Glucose Co-transport system of the small intestin and kdney (SYMPORT) Sodium gradient (influx of Na+) provides the energy for the entry of glucose against concentration gradient
  • Na+-Ca2+-Excange: inward flow of sodium down its concentration gradient drives outward flow of Ca2+ up its concentration gradient (ANTIPORT)
  • Na+--H+-Exhange: influx of sodium down its concentration gradient leads to cell alkalisation by removin H+ (ANTIPORT) - cell pH increases
  • Na+-K+-ATPase: maintain cellular concentrations of Na+ and K+ (antiport)

11

Describe the differences between Primary and Active Transport (using examples)

  • Na+ Pump pumps 3Na+ ions outwards, 2K+ ions inwards against the respective concentration gradients, at the hydrolysis of 1 ATP leaving behind a negative charge inside the cell. If the pump runs in reverse, it can act as an ATPgenerator.
  • In mitochondria, a gradient of H+ ions is employed to drive ATP synthesis via an ATP-dependent proton transporter.
  • Sometimes the transport of one substance is linked to the concentration gradient for anothe via a Co-transporter. This is known as Secondary Active Transport as the primary energy source (e.g. Hydrolysis of ATP) is used indirectly.
  • A primary active transporter example is Ca2+-ATPase.  Hydrolysis of ATGP releases free energy to drive Ca2+ out of the cell against its concentration gradient.
  • Membrane transporters may be driven by gradients of ATP, phosphoenolpyruvate, proton and sodium ions, light and high potential electrons. Often a sodium gradient is employed

12

Describe the free ion distribution across the cell membran

NB: for K+ an increase to 6-7mM extracellular can have very dangerous clinical consequence

13

What is a uniport?

Transporter transports ONE solute molcule species from one side of the membrane to the other

14

What is a Symport?

When transfer of one solute molecule depends on the simultaneous or sequential transfer of a second solute in the same direction

A Symport is also a Co-transporter

15

What is an Antiport?

When the transfer of one solute molecle depends on the simultaneous or sequential transfer of a second solute molecule in the opposite direction.

16

Describe the Sodium Pump

  • The Na+-K+-ATPase pump s present in all cells.
  • Plasma membrane associated pump
  • Antiport
  • Uses ATP to pump ions (active transport)
  • 25% of Basal Metabolic Rate is used for the pump
  • Called a P-type ATPase (ATP phosphorylated Aspartate residue within protein, driving a conformational change and producing a phosphoenzyme intermediate)
  • The binding of Ouabain to the alpha subunits inhibits the pump
  • Pump created an enormous gradient - creates high intracellular [K+] but not really responsible for membran potential (only generaes about -5--10mV)

 

17

Why is the Sodium Pump so important?

  • Forms Na+ and K+ gradients which are necessary for electrical excitability

  • Uses energy from hydrolysis of ATP to move 2K+ into the cell and 3 Na+ out of the cell- creates a high intracellular [K+]

  • Drives Secondary Active Transport:

    Control of pH

    Regulation of cell volume

    Regulation of Ca2+ concentration

    Absoprtion of Na+ in epithelia

    Nutrient uptake, e.g. glucose from the small intestine

     

18

Describe Ca2+ Transport

Ca2+-Mg2+-ATPase is a primary active tranporter (uniport)

Na+-Ca2+-Exchanger is a secondary active transporter (uss Na+ gradient which is generated from hydrolysis of ATP) (antiport)

high capacity = high Vmax

19

Describe Transporters in Cystic Fibrosis

  • CFTR is a transporter forChloride
  • Transport of Na+ out of cell by Na+/K+ pump allows for the Symport of 2Cl- into the cell with N+ and K+
  • The chloride passes across the cell via the CFTR transporter into the lumen of the alveoli and that generates an osmotic potential which drags water from the blood into the lumen of the alveoli, keepin the mucus mobile.
  • Defctive CFTR transporter in CF sufferers prevents the passage of Cl- out of the cell - Cl- accumulates within the lumen of the cell. Water moves into the cell so the mucus becomes viscous and thick.
  • Physiotherapy mobilises the mucus
  • this happens in all epithelial cells including in the gut and vas deferens
  • CHLORIDE TRANSPORT IS IMPAIRED

20

Descibe Transporters in Diarrhoea

  • In the small intestine, regulation of CFTR can change
  • Protein Kinase A can phosphorylate CFTR and increase its activity (so it becomes overly active) increasing the rate of efflux of chloride so all the transport mechanisms work to bring more chloride into the lumen (via acoss the cell).
  • This creates an increased osmotic potential. Water is dragged across the cell membrane resulting in diarrhoea from the small intestine.
  • Water is normally present in faeces to keep them soft but now that there is excess water, you get symptoms of diarrhoea.
  • It takes just one transporter to be faulty to impair function of the cell.

21

Why is the control of intracellular [C2+] important and what transporters are involved?

  • Important because high intracellular calcium is toxic to cells and can lead to calcium necrosis/induced cell death
  • 20,000 fold difference in levels across the plasma membrane
  • Cells signal by small changes in intracellular [Ca2+]
  • Primar Active Transporters: PMCA, SERCA
  • Secondary Active Transporters: NCX
  • Facilitated Transport: Mitochondrial Ca2+ Uniports (operate at high intracellular [Ca2+] to buffer potentially damaging [Ca2+])

22

Descibe the role of K+ Channels

  • Voltage-sensitive
  • Sodium pump creates high intracellular [K+]
  • K+ diffusion through channels down is concentration gradient is mainly responsible for membrane potential (-70mV)

23

Describe the role of PMCA

  • Plasma Membrane Ca2+-ATPase
  • Transporter expels Ca2+ out of the cell (high affinity, low capacity - removes residual Ca2+)
  • Expels Ca2+ in exchange for H+
  • Uses ATP
  • Antiport

24

Descibe the role of SERCA

  • Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA)
  • Accumulates Ca2+ into the SR/ER (intracellular stores) in exchange for H+
  • High affinity low capacity
  • Removes residual Ca2+
  • Uss ATP
  • Antiport

25

Describe the Role of NCX

  • Sodium Calcium Exchaner
  • Uses the Na+ gradient set up by the Sodium Pump
  • Antiport
  • Low affinity, high capacity
  • Removes most Ca2+
  • Electrogenic - current flows in the direction of the Na+ gradient
  • Role in expelling intracellular Ca2+ during cell recovery
  • Activity is membrane potential dependent (depolarised membrane potential reverses mode of operation - exchanges 3Na+ for 1 Ca2+ in - conributes influx of Ca2+)

26

Describe the role of NCX in Ischaemia

  • ATP is depleted in Ischaemia
  • This leads to a low Na+ gradient (Sodium pump inhibited) so there is no drive to drive NCX
  • The exchanger reverses mode of operation which leads to high intracellular [Ca2+] (as Na+ moves out and Ca2+ moves in)
  • Potentially toxic

27

Describe the role of NHE

  • Na+/H+-Exchanger
  • Exchanges extracellular Na+ for intracellular H+
  • Electroneutral - 1:1 exchanged: 1Na+ moves in, 1 H+ moves out
  • Regulates cell pH
  • Regulates cell volume
  • Important in retention of Na+ in kidney
  • Activated by growth factrs
  • Inhibited by Amiloride (drug)

28

Describe the Control of Cell pH

  • Acid Extuders: NHE, Sodium Bicarbonate Cotransporter
  • Base Extruders: Anion Exchanger (band 3 protein in erthrocyte membrane),
  • When cellular buffering capacity is exceeded, cellular pH is controlled by the activity o a variety of plasma membane transporters.
  • Acidification can be opposed by expelling H+ ions or the inward movement of bicarbonate ions.
  • Alkalinisation can be opposed by expelling bicarbonate ions via the anion exchanger

29

Describe the role of the Sodium Bicarbonate Co-Transporter (NBC)

  • AKA Na+ dependent Cl-/HCO3- Exchanger
  • Mixed Transporter
  • Secondary active transport using Na+ gradient set up by Sodium pump to control the acidity of a cell
  • Acid out (H+)
  • Base in (HCO3-)
  • Raises intracellular pH
  • Also involved in regulating cell volume

30

Descrie the role of AE

  • Anion Exchanger
  • Cl-/HCO3- Exchanger
  • Base Extruder
  • Removes HCO3- (base) from cell
  • Lowers intracellular pH
  • Acidifies cell
  • Involved in cell volume regulation as well