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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