K+ channel modulators

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different types of potassium channels..their structure and functions..

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K+ channel modulators

  1. 1.  Introduction  K+ channel architecture  Selectivity filter  Ion permeation  K+ channelopathies  Drugs
  2. 2.  Ion channels are integral proteins  Plays a vital role in functioning of a cell  Genetic identification of ion channels has improved our understanding……….  Ion channels enzymes…
  3. 3. Intracellular volume is ~10–12 Ion permeate at the rate of 107/s Intracellular k+ concentration 100 mM After one sec there will be no k+ in cell
  4. 4. Hence to b effective in altering the membrane potential …………….  The opening & closing of channel should be brief and fast………. Structural basis of permeation & selectivity
  5. 5.   -KcsA 4 sub units are clustered to form to form ion permeation pathway..  About 78 human genes have been identified yet…..  K+ channels are tetramers composed of four alpha subunits..
  6. 6. CLASSIFICATION OF K+ CHANNELS 6TM/P 22TM/P 8TM/2P 4TM/2P
  7. 7.  2TM/P is essentially a universal feature of k+ channel  it has amino tetramerization domain, carboxy terminal, protein interacting domain..  standard nomenclature of these channels was proposed by Nomenclature and Drug Classification International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug classification (NCIUPHAR)
  8. 8. 2 TM Family
  9. 9. 4 TM Family
  10. 10. 6 TM Family
  11. 11.  How are k+ channels selective…..? Selectivity filter T V G Y G ~12 Å ~2.5 Å Series of stereo chemical check points
  12. 12. Ion permeation  k+ channel should operate under two constraints….. strictly selective & quick  Strategies Knock-on ion conduction Dehydration barrier Two conduction states
  13. 13. Knock-on ion conduction The dehydration barrier
  14. 14. Two conduction modes  Higher conduction state 500 ps k+ more than 20mM  Lower conduction state less than 20mM
  15. 15. K+ Channelopathies  Cardiac diseases (KvLQT1) CNS diseases (KCNA1) Deafness (KCNQ4) Renal diseases(KCNJ1) Metabolic diseases (SUR1)
  16. 16. DRUGS K+ Channel openers
  17. 17. K+ channel blockers

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