Desensitisation and Ion channel

• Desensitisation


  Response to a drug decreases when taken continuously or repeatedly
• Tachyphylaxis (Desen)


  Response to drug diminishes rapidly - neurotransmitter depletion and receptor phosphorylation
• Tolerance (Desen)


  Response decreases over longer time - days or weeks - decreased receptor number and physiological changes
• Desensitisation mechanisms


  • Change in receptors
  • Receptor translocation
  • Exhaustion of mediators
  • Altered drug metabolism
  • Physiological adaptation (homeostasis)
  • Active extrusion from cells (cancer chemotherapy)
• Desensitisation mechanism: Change in receptors


  1. Ion channel receptors display rapid desensitisation and it causes a conformational change in receptors

  2. If taken continuously (acetylcholine) there is a sustained response that diminishes overtime while if taken once there is a big spike in response
• Desensitisation mechanism: Exhaustion of mediators


  Amphetamine releases noradrenaline from nerve terminal in place of noradrenaline which become depleted → no NoraA there is no NT it became desensitised
• Desensitisation mechanism: Altered drug metabolism


  1. Increase metabolism of ethanol and barbiturates results in lower plasma concentration

  2. Metabolism occurs quickly and reduces the effect of drugs because of lower plasma drug levels
• Desensitisation mechanism: Physiological adaptation (homeostasis)


  1. Thiazide diuretics lower blood pressure (treats BP and increases urine flow)

  2. Limited by activation of renin-angiotensin system
• Desensitisation mechanism: Active extrusion from cells (cancer chemotherapy)


  If extruded then its desensitised and no longer active
• 4 receptor superfamilies


  • Ion channels (VERY FAST)
  • G protein coupled receptors (FAST)
  • Enzyme linked (SLOW)
  • Nuclear (DNA linked, intracellular) (VERY SLOW)
• Major types of ion channels

  • Ion channel receptor- ligand-bind reg opening/closing
  • Voltage gated ion channel - change in potential or V-gradient regulates channel opening and ion conductance
  • Second messenger-regulated ion channel - ligand binding to g protein coupled receptor leads to second messenger generation it also regulates opening and ion conductance
• Ion channels


  • Ions cannot cross membrane
  • -30 to -80 at resting conditions
  • Open and close to regulate flow - depolarisation/hyperpolarization
  • Play role in neurotransmission, cardiac conduction, muscle contraction and sections
• Membrane potentials


  • Depend on balance of ions in/out-side of cell
  • Neg: Cl
  • Pos: Na, K, Ca2+
• Ion channels characterised by


  • Selectivity of ion species
  • Pore size and lining
  • Cations and anions
  • Gating properties (controls opening and closing)
  • Structure
• The rate and direction of movement in an ion channel depends on

  The electrochemical gradient and membrane potential
• Patch clamp recording


  • Measures flow of ions through a channel
  • Flow of current through a single open channel is in pA (picoamp = 10-12 amps)
  • Agonist binding causes repeated channel openings (graph on slides)
• Ion channel activity is characterised by


  • Ion currents
  • Freq of channel openings
  • Different agonists cause different frequencies of channel opening
• Ion channel receptors subunits how many and where


  • 4-5 membrane spanning subunits
  • Both intra and extra- cellular regions
  • And a membrane spanning section
• Can ions cross membrane when channels are closed
• Protein subunits that make up an ion channel receptor


  • Alpha
  • Beta
  • Gamma
  • Delta
  • The composition determines the properties
• Typical ion channel receptor subunit structure


  • 4 membrane spanning alpha helices
  • Amino and carboxyl ends both extracellular
  • Binding domain
• Ligand binding example


  Nicotinic acetylcholine receptor
• Ligand binding channel open


  1. When two agonist molecules bind to two alpha subunits to cause channel opening

  2. Needed to activate receptor

  3. 5 subunits turn in relation to each other

  4. Then the channels open
• Endogenous agonists examples


  • Acetylcholine, g-aminobutyric acid (GABA)
  • Glycine, glutamate, 5-hydroxytryptamine (5-HT)
• Activation causes what changes in cell membrane potential


  Depolarisation or hyperpolarisation
• Acetylcholine as an agonist example


  • Acetylcholine stimulates
  • Nicotinic acetylcholine receptors - ion channel receptor acetylcholine - depolarisation, excitatory response
  • Muscarinic acetylcholine receptors
• Nicotinic acetylcholine receptors are found where


  • Skeletal neuromuscular junction
  • Ganglion cells in the peripheral nervous system
  • Neurons in the central nervous system
• Muscarinic acetylcholine receptors are what type

  G protein-coupled receptor
• Acetylcholine will cause sodium influx


  The causes depolarisation and fire an action potential for muscle cell contraction
• Agonists: g-aminobutyric acid (GABA)


  • GABA is formed from glutamate in the brain
  • GABA is an inhibitory transmitter in many central nervous system pathways
  • Cause Hyperpolarisation
• 3 types of GABA receptor

  • GABA(A) and (GABA(C)) – ion channel receptors
  • GABA(B) – G protein-coupled receptor
• Agonists: glycine


  • Amino acid – stimulates glycine receptors
  • Inhibitory neurotransmitter mainly in the spinal cord ->hyperpolsation (-)
  • Strychnine – surmountable antagonist at glycine receptors
  • Strychnine - convulsions and muscle contraction
• Agonists: glutamate


  • Amino acid – stimulates glutamate receptors
  • Fast acting excitatory neurotransmitter in the CNS
  • Depolarises (+)
• Agonists: 5-hydroxytryptamine (5-HT, serotonin)


  • Many actions including increase gastrointestinal motility, vasodilation, platelet aggregation
  • Agonist at different receptor types including ion channel receptors in the nervous system
• Strychnine


  • Surmountable antagonist at glycine receptors
  • Convulsions and muscle contraction
  • Will bind to glycine receptors to prevent gly from bindto and therefore prevent inhibition actions
• GABAA receptors are ionotropic receptors that allow for chloride ions to flow into a cell upon agonist (GABA) binding. What do the Cl ions do?


  Chloride ions moving into a cell typically decrease second messenger signaling and produce inhibitory effects
• Neuromuscular junction location


  Between nerve and skeletal muscle fibre. In an adult 1 motor neuron can activate each skeletal muscle fibre
• Neuromuscular junction signal pass (NJ1)


  Signals pass along motor nerve to presynaptic boutons. The structure will increase surface area across which the neurotransmitter can be release
• Skeletal nerve will release (NJ2)


  Acetylcholine which crosses the synaptic cleft and interacts with nicotinic acetylcholine receptors on the muscle
• Myelin


  Insulation to speed up the impulse