Membrane Permeability and Intracellular Homeostasis 1 and 2

Membrane Permeability and Intracellular Homeostasi

Membrane Permeability and Intracellular Homeostasis 1 and 2

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Membrane Permeability: Pure Phospholipid Bilayer

  • Polar material - ions, charged drugs, peptides
  • Apolar material - glucose, fats, uncharged drugs

Membrane Permeability

Cellular Environment and Membrane Permeability

  • Resting membrane potential: -70mV
  • Plasma membrane acts as a barrier to solute movement

Membrane Proteins

  • Intrinsic membrane proteins
    • Ion channels (e.g. Na+, Ca2+, K+ channels)
    • Receptors for neurotransmitters (e.g. acetylcholine)
    • Pumps/transporters (e.g. Na+/K+ pump, p-glycoprotein, Cystic Fibrosis Transmembrane Regulator (CFTR))
  • Extrinsic membrane proteins
    • E.g. recognition or adhesion molecules
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Ion Channels vs. Ion Pumps

  • Ion channels
    • Ions rush down gradients of concentration or electrical potential
    • Passive
  • Ion pumps
    • Actively push ions against a gradient and therefore build up the gradient
    • Use ATP
    • One pump can transport two ions Na+/K+
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Membrane Ion Channels

  • Na+ channel
  • Ca2+ channel
    • Amlodipine
  • K+ channel
  • Cl- channel
  • Ion channels are water-filled pores that allow ions to cross the membrane and move down their concentration gradient
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When Channels go Wrong - Channelopathies

  • Cystic fibrosis 
    • Cl- channel
  • Benign familial neonatal convulsions
    • K+ channel subclass
  • Cardiac arrhythmias
    • K+ channel subclasses
    • Na+ channel subclasses
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Plasma Membrane Receptors

  • Ionotropic receptors (ligand-gated ion channels)
    • e.g. nicotinic acetylcholine receptor

Receptors as Pharmaceutical Targets

  • Largest target group
  • Roughly 25% of licensed pharmaceuticals target receptors
  • Drug class: beta-2-adrenoceptor agonists
  • Examples: salbutamol, salmeterol
  • Mechanism of action: binding of beta-2-adrenoceptors results in smooth muscle relaxation and opening of the airways
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Plasma Membrane Receptors

  • Direct - ionotropic receptors
  • Indirect - intracellular signalling molecules are involved
  • The signal is not membrane-limited
  • Signal transduction is slower
  • Transduction is subject to more regulation 
    • more steps involved
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Bronchodilators

Secondary Messengers

  • Intracellular switch proteins
  • Many proteins bind GTP rather than ATP 
  • Often termed G-proteins or GTPases
  • Active when bound to GTP
  • Inactive when bound to GDP
  • Can hydrolyse GTP to GDP

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Signal Transduction and Cell Signalling

  • The mechanisms whereby a command is executed within a cell, i.e. how an external signal generates an intracellular message
  • For example:
    • How an action potential causes transmitter release
    • How acetylcholine phosphorylates ion channels
    • How hormone release is controlled - insulin
    • How agonists modify cell growth - EGF
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Signal Transduction and Cell Signalling

  • Signal transduction:
    • A number of different schemes are employed
    • Comman molecules (transmitters)
    • Various effectors (executing molecules)
    • G-proteins (middle management)
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Transporters/Pumps

  • Membrane transporters/pumps move solutes against their concentration gradients
  • In order for this to occur an energy source is required (usually ATP)
  • They are present in the plasma membrane and organelles (i.e. mitochondria)
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Types of Transporters

  • Uniport - Ca2+ pump
  • Symport - Glucose-Na+ coupled transport in epithelia
  • Antiport - Na+/K+ pump (all cells)

Na+/K+ Pump

  • Example of a P type ATPase
  • Present on plasma membrane of all cells in the body
  • An example of an antiporter
  • Ion transport is uphill, against electrochemical gradients
  • It is therefore active transport
  • It uses energy derived from ATP hydrolysis to drive ionic movement
  • Target of Digoxin - inhibits ATPase activity
  • 3Na+:2K+ stoichiometry
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Symport in Action in the Intestine

  • Na+-glucose coupled transport across the apical membrane of the enterocyte

Ca2+ Regulation

  • Ca2+ regulation is achieved by both an antiport and a uniport
  • As a result intracellular Ca2+ is kept very low (~100nM)
  • Extracellular 1.5-2.0mM

Apoptosis vs. Necrosis

Apoptosis

  • Sometimes termed cellular suicide or programmed cell death
  • Allows removal of specific cells for various reasons
  • Intrinsic (cell divides) and extrinsic (told by other cells) pathways
  • Results in blebbing of the membrane and formation of apoptotic bodies which are cleared by immune cells, i.e. macrophages
  • Intimately linked with intracellular Ca2+ and mitochondrial Ca2+ levels
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Apoptosis

Necrosis

  • Traumatic cell death caused by acute cellular injury
  • Can be induced by ischaemia/hypoxia, poisons, lytic viruses etc.
  • Results in complete cellular lysis
  • Complete lysis releases cytotoxic components into the extracellular space which results in inflammation and an immune response
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Apoptosis vs. Necrosis

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