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Voltage Gated Calcium Channels-Function And Regulation

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Voltage Gated Calcium Channels-Function And Regulation

  1. 1. Credit Seminar On Voltage-Gated Calcium Channels Function And Regulation By: Ravi Dhiman M.Sc. (ABC) NDRI, Karnal 1
  2. 2. Introduction  CaVs mediate calcium influx in response to membrane depolarization  Regulate intracellular processes such as contraction, secretion, neurotransmission and gene expression in many different cell types  They are members of a gene super family of transmembrane ion channel proteins that includes voltage-gated potassium and sodium channels  CaVs are under intense pressure to control calcium influx and to detect and respond to changes in intracellular calcium concentrations 2
  3. 3. Brief History • Discovered accidentally by Paul Fatt and Bernard Katz in crustacean muscles ( Fatt & Katz, 1953 ) • Carbone and Lux first used the term LVA and HVA in mammalian sensory neurons (Carbone & Lux, 1984) • Kurt Beam identified voltage-gated calcium channels as the voltage sensors in skeletal muscles ( Beam et al., 1992 ) 3
  4. 4. What are CaVs? • Voltage-gated calcium channels (CaVs) are large , multi-subunit, macromolecular machines • Control calcium entry into cells in response to membrane potential changes Felix Findeisen et al., 2010 4
  5. 5. What is channel gating?  Gating describes the opening and closing of channels  Ca2+ channels open (or activate) within one or a few milliseconds after the membrane is depolarized from rest  Close (deactivate) within a fraction of a millisecond following repolarization 5
  6. 6. Signal transduction by voltage-gated Ca2+ channels Catterall W A 2011 6
  7. 7. CaVs Classification  First evidence that there might be more than one type of calcium channel was first reported by Hagiwara in 1975 using egg cell membrane of a starfish  They were initially divided into two classes HVA & LVA Ca2+ channels  HVA Ca2+ channels are further divided into L, N, P/Q & R-types channels, while LVA Ca2+ channels consists of only T-type channels  R-type is occasionally classified as ( IVA ) channels A.C. Dolphin et al., 2006 7
  8. 8. Calcium Channel Dendrogram 8
  9. 9. Catterall W A 2011 9
  10. 10. Cav global architecture Glenn F. King 2007 10
  11. 11. β Subunit Contains Guanylate Kinase domain and SH3 domain Has a mol. wt. of 55 kDa GK domain binds α1I-II intracellular loop Stabilizes α1 and helps to traffic to membrane Yue et al ., (2004) 11
  12. 12. α2δ Subunit The α2δ gene forms two subunits: α2 and δ (which are both the product of the same gene) They are linked to each other via a disulfide bond The α2 is extracellular glycosylated The δ subunit has a single trans-membrane region Co-expression enhances the level of expression of the α1 subunit 12
  13. 13. γ Subunit • γ- Has 4 transmembrane helices • Does not affect trafficking and for the most part, is not required to regulate the channel complex – Found in skeletal muscles – May have an inhibitory effect on calcium currents 13
  14. 14. Calcium Dependent Gene Transcription •NFAT (nuclear factor of activated T cells) •GSK3 (glycogen synthase 3) •Casein Kinase 1 • NMDA (N-methyl-D-aspartate) receptors (NMDARs) Anne E. West et al.,2002 14
  15. 15. Regulation of Smooth Muscle Contraction R. 2003 Clinton Webb 15
  16. 16. Structural Insights into Ca2+ -CaM Regulation of CaVs Felix Findeisen et al., 2010 16
  17. 17. Regulation of CaVs By Synaptic Proteins • Calcium entry through neuronal voltage-gated calcium channels into presynaptic nerve terminal is a key step in synaptic exocytosis • In order to receive the calcium signal and trigger fast, efficient and spatially delimited neurotransmitter release, the vesicle-docking/release machinery must be located near the calcium source • The binding of synaptic proteins to pre-synaptic calcium channels modulates channel activity to provide fine control over calcium entry, and thus modulates synaptic strength 17
  18. 18. Atlas D 2010 18
  19. 19. c Atlas D 2010 19
  20. 20. Conclusion • Ca2+ channels are the signal transducers that convert electrical signals in the cell membrane into an increase in the intracellular second messenger Ca2+ and thereby activate many crucial intracellular processes including contraction, secretion, neurotransmission and regulation of enzymatic activities and gene expression • These channels are complex proteins containing five distinct subunits, each of which is encoded by four to ten separate genes • Ca2+ channels are tightly regulated by a range of signal transduction pathways in addition to regulation by their intrinsic, voltage-dependent gating processes 20
  21. 21. References • Catterall WA. (2011) Voltage gated Ca2+ channels .Cold Spring Harb Perspect Biol. • Felix Findeisen and Daniel L. Minor, Jr. (2010) Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Landes Bioscience,6:459-474 • Atlas D. (2010) Signaling role of the voltage-gated calcium channel as the molecular on/off-switch of secretion. Cell Signal,22:1597-1603 • Annette C. Dolphin (2006) A short history of voltage-gated calcium channels. British Journal of Pharmacology,147: S56-S62 21
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