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Voltage-Gated K + Channels

Voltage-Gated K + Channels. MK Mathew NCBS, TIFR UAS – GKVK Campus Bangalore. IBRO Course in Neuroscience Center for Cognitive N euroscience & Semantics, University of L atvia Riga, L atvia August 21-August 29, 2013. PROPERTIES OF VOLTAGE-GATED ION CHANNELS. Voltage sensitive

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Voltage-Gated K + Channels

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  1. Voltage-Gated K+ Channels MK Mathew NCBS, TIFR UAS – GKVK Campus Bangalore IBRO Course in Neuroscience Center for Cognitive Neuroscience & Semantics, University of Latvia Riga, Latvia August 21-August 29, 2013

  2. PROPERTIES OF VOLTAGE-GATED ION CHANNELS • Voltage sensitive • Requires voltage-sensing apparatus • Requires transduction machinery • High Throughput: 108 ions/second • Protein supports an aqueous column traversing the membrane • Discriminates between Na+ and K+ • Requires a selectivity filter

  3. 1982 Noda … Numa Nature AChR a-subunit cloned from peptide information • 1983 Noda … Numa Nature All AChR subunits cloned • 1984 Noda … Numa Nature Na channel a-subunit cloned • 1987 Stuhmer .. Numa Eur J Biophys Xenopus expression Na channel • 1989 Stuhmer Conti .. Numa Nature S4 mutations in Na channel

  4. Sodium Channel

  5. 1982 Noda … Numa Nature AChR a-subunit cloned from peptide information • 1983 Noda … Numa Nature All AChR subunits cloned • 1984 Noda … Numa Nature Na channel a-subunit cloned • 1987 Stuhmer .. Numa Eur J Biophys Xenopus expression Na channel • 1989 Stuhmer Conti .. Numa Nature S4 mutations in Na channel • 1987 Kamb Iverson Tanouye Cell • 1987 Papazian … Jan Science Shaker Cloning • !988 Pongs … Ferrus EMBO J

  6. Xenopus oocytes Two Electrode Voltage clamp

  7. ELECTROPHYSIOLOGICAL PROPERTIES OF HUMAN K+ CHANNELS

  8. hKv1.4

  9. KcsA Doyle et al., Science 1998; 280: 69

  10. Doyle et al., Science 1998; 280: 69 Jiang et al., Nature 2002 417; 523

  11. Gary Yellen

  12. KcsA Doyle et al., Science 1998; 280: 69

  13. Zhou .. MacKinnon (01) Nature

  14. Varma & Rempe (2007) Biophys J 93:1093–1099

  15. Zhou .. MacKinnon (01) Nature

  16. Payandeh .. Catterall (2011) Nature

  17. RajGanesh et al (2000) Proteins

  18. KcsA Doyle et al., Science 1998; 280: 69

  19. Kv 1.2 Crystal Structure MacKinnon ,2005

  20. … Catterall (2006) PNAS

  21. Pathak .. Isacoff (2007) Neuron

  22. Sequence Alignment of The S4-S5 Region S4 S5 Ken (1991) PNAS

  23. L1 L2 L3 L4 L5 Mutant V1/2 (mV) Wt 1±5 V1 100±6 V2 69±7 V3 -5±2 V4 -22±3 V5 -7±7 V2A3 32±5 V1/2 Val/Ala mutations in Shaker Phenylalanine mutations in hKv 1.4 McCormack et al., (1991) Judge et al., (2002) McCormack et al (91) PNAS

  24. Bezanilla (2000) Physiol Rev 80, 555 - 592

  25. Gating charge Sensor Movement Po Schoppa Sigworth (98) JGP

  26. Kv 1.2 Crystal Structure MacKinnon ,2005

  27. L312M-L326V DV1/2 = 0 mV V406L–L312M DV1/2 = -42 mV A305L-L312M DV1/2 = +18 mV Sanjeev

  28. Sanjeev, Nagarajan J Physiol

  29. OPEN STATE Sanjeev, Nagarajan

  30. CLOSED STATE

  31. CLOSED OPEN Sanjeev, Nagarajan J Physiol

  32. Gating charge Po Ledwell Aldrich (99) JGP

  33. Gating charge Po Ledwell Aldrich (99) JGP

  34. ACTIVATED STATE

  35. CLOSED ACTIVATED OPEN

  36. Sanjeev, Nagarajan J Physiol

  37. Kaczmarek Nature Reviews Neuroscience7, 761–771 (October 2006) | doi:10.1038/nrn1988

  38. + + + + S1 S2 S3 S4 S5 p S6 T1 Ball KCNRG (monomer)n ? T1 KCNRG : K (Potassium) / CN (Channel) / RG (Regulator) D.V. Ivanov et al./FEBS Letters 539 (2003) 156-160

  39. 5um Surface Expression Analysis KCNRG reduces Surface targeting of hKv 1.4 Hyder (2010)

  40. KS Krishnan 1976

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