Ion channels in heart

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  1. How many subunits in a sodium channel? What do they do?
    • a, beta1, beta2
    • alpha forms pore and alone can produce a functional channel
    • others modulate
  2. Structure of alpha subunit of sodium channel
    4 homologous domains, with 6 membrane spanning alpha-helix subunits each, arranged to form a pore
  3. 'Gates' within alpha subunit of sodium channel
    • m gate shut in resting state (made of S4 units)
    • h gate shut in inactivated state
  4. Parts of the alpha subunit and what they do
    • S4 (esp I, II, III): voltage sensor: positively charged, rotate outwards in response to membrane depolarisation - m gate
    • Intracellular loop between S3 and S4: h gate responsible for inactivation - swings into internal mouth of channel and closes it
    • Extracellular loop between S5 and S6, and S6 in domain IV: selectivity filter
  5. Drugs acting on sodium channels
    • Local anaesthetics stabilise inactivated state
    • Bind to intracellular surface of channels
    • Can be used as antidysrhythmics and anti-epileptics
  6. How many subunits in a VGCC?
    • 5: a1, a2, beta, gamma, delta
    • a1 similar to a subunit of sodium channels: shows same voltage-sensing, selectivity, inactivation characteristics
  7. 3 classes of drugs acting on VGCCs and an example of each
    • Dihydropyridines eg nifedipine
    • Benzodiazepines eg diltiazem
    • Phenylalkylamines eg verapamil
  8. DHP binding sites
    • 2: 1. segment 6 and associated S5-S6 loop in domain III
    • 2. closely related to phenylalkylamine binding site in S5-6 loop on domain IV
  9. Benzothiazepine binding
    • Block from outside
    • Bind in different place from DHPs, but modulate DHP binding
  10. Phenylalkylamine binding
    • To S6 and S5-6 loop
    • Determined via photoaffinity labelling
  11. Features of L type channels
    • Require large depolarisation to open (30mV)
    • Stay open for a long time, inactivate slowly
    • High single channel conductance (22-27 pS)
    • Found in almost all excitable cells
    • activity enhanced by NA and Adr - leads to channel phosphorylation
    • sensitive to DHP drugs which bind to inactivated channels but show no use dependence
  12. Features of T type channels
    • Requre small depolarisation to open (10-20mV)
    • Transient opening, rapid inactivation
    • Low single channel conductance (10-20mV)
    • Resistant to DHPs
    • Blocked by Ni2+
    • Found in nodal pacemaker tissue
  13. 2 roles of K channel in heart
    • Repolarisation at end of action potential
    • Stabilisation and modification of resting potential in atria and ventricles
  14. Structure of K channels
    • Kv protein same as 1 Na subunit: 6 TM alpha-helix domains
    • Isolated from Shaker mutant
    • Possibly 4 Kv channels needed to create a functional channel?
  15. 2 types of inactivation of K channels
    • 1. ball and chain
    • 2. P type - movement of residues near extracellular surface of pore
  16. Most important current for maintenance of resting potential in heart
    IK1 current: inward rectification during depolarised phase
  17. Describe the Kir channels that carry the IK1 current
    • Open at hyperpolarised potentials, allow K to flow in
    • Closed at depolarised potentials, prevent K loss
    • Closed by intracellular polyamines eg spermine
    • 2 membrane spanning domains
  18. 3 types of Kir channels
    IK1, IK-ACh, IK-ATP
  19. Describe IK-ACh channels
    • Kir 3.1 aka HGIRK1 (human G protein activated inward rectifying potassium channel)
    • Activated by ACh ? M2 receptors via �? subunit
    • Causes hyperpolarisation
  20. Describe IK-ATP channels
    • Open with low intracellular ATP, Close with high intracellular ATP
    • Influenced by sulphonylureas
    • Important in protection from ischaemia and antihypertensives
  21. Minimum membrane potential in SA and AV nodes
  22. What produces LQT3?
    A mutation in the loop connecting domains III and IV of cardiac voltage gated sodium channels
  23. What conditions are associated with SADS?
    Hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome
  24. Channels underlying If
    • HCN (Hyperpolarisation activated and Cyclic Nucleotide gated channels)
    • Open on hyperpol, close on depolarisation
    • Almost as permeable to Na as they are to K: hyperpol leads to slow depolarisation
    • Same S1-S6 structure
  25. Main difference between pacemaker nodal cells and atrial/ventricular cells
    Presence of funny current, absence of voltage gated sodium channels
  26. Location and broad function of autonomic receptors
    • beta-adrenergic increase cAMP: throughout heart
    • M2: on nodes
  27. Effect of catecholamines on heart - mimicked/blocked by?
    • beta1 increase cAMP -> increase ICa-L and ICa-T: via PKA phosphorylation
    • mimicked by Na/Adr/isoprenaline/cholera (Stimulates Gs), forskolin (Stimulates AC)
    • Blocked by propanolol, atenolol
    • Slow time course: 5s latency, 30s to reach maximum
  28. 4 actions of cAMP in heart
    • 1. PKA phosphorylation of ICa-L and Ica-LT
    • 2. ryanodine receptors are sensitised -> increased Ca release from ER
    • 3. If is activated at more positive levels
    • 4. Delayed-rectifier K channels are enhanced -> shorter APs
  29. 3 effects of ACh in heart
    • 1. nodal calcium currents reduced: negative chronotropic (not inotropic as these Ca channels are not found in the main heart muscle bulk)
    • 2. If is activated at more negative levels
    • 3. IK-ACh stimulated: hyperpolarisation
  30. 2 types of local anaesthetics, effect on metabolism, examples
    • ester: substrate for circulating cholinesterases, breaks down quickly: procaine, benzocaine
    • amide: longer lasting: lidocaine
Card Set:
Ion channels in heart
2012-12-31 10:35:09
moda henderson ion channel sodium potassium calcium

Voltage gated ion channels in cardiac muscle cells: structure and function
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