voltage gated calcium channels-function and regulation
TRANSCRIPT
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Credit Seminar On
Voltage-Gated Calcium Channels Function And Regulation
By: Ravi DhimanM.Sc. (ABC)
NDRI, Karnal
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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
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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 )
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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
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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
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Signal transduction by voltage-gated Ca2+ channels
Catterall W A 2011
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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
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Calcium Channel Dendrogram
Catterall W A 2011 9
Cav global architecture
Glenn F. King 200710
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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)
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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
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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
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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
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Regulation of Smooth Muscle Contraction
R. Clinton Webb 2003
Structural Insights into Ca2+ -CaM Regulation of CaVs
Felix Findeisen et al., 201016
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Regulation of CaVs By Synaptic Proteins
• Calcium entry through neuronal voltage-gated calcium channels into pre-
synaptic 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
18 Atlas D 2010
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c
Atlas D 2010
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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
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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
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Thanks