Alternate Splicing in the Cytosolic II–III Loop and the Carboxy Terminus of Human E-type Voltage-Gated Ca Channels: Electrophysiological Characterization of Isoforms

Pereverzev, Alexey; Leroy, Jérôme; Krieger, Andreas; Malécot, Claire O.; Hescheler, Jürgen; Pfitzer, Gabriele; Klöckner, Udo; Schneider, Toni

doi:10.1006/mcne.2002.1179

Cited by 53 publications

(69 citation statements)

References 35 publications

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“…A homologous alternatively spliced exon whose expression is regulated is also present in the Ca V 2.3 gene (14,17,18). Functional studies of Ca V 2.3 channels that contain this exon indicate that it regulates the Ca sensitivity of certain channel properties (19,20).Here, we demonstrate that Ca V 2.2 splice isoforms that contain and lack exon 18a differ significantly in their susceptibility to inactivation during trains of action potential waveforms. The presence of exon 18a protects the channel from entry into closed-state inactivation, and this likely reduces cumulative inactivation.…”

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confidence: 59%

“…A homologous exon is also present in the Ca V 2.3 gene. Its function is not known, but studies have linked it to Ca-sensitive regulation of the channel (18)(19)(20)31). Exon 18a of Ca V 2.2 is expressed abundantly in caudal regions of the mammalian nervous system and in peripheral nerve ganglia (15).…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing

Thaler

Gray

Lipscombe

2004

Proc. Natl. Acad. Sci. U.S.A.

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The CaV2 family of voltage-gated calcium channels, present in presynaptic nerve terminals, regulates exocytosis and synaptic transmission. Cumulative inactivation of these channels occurs during trains of action potentials, and this may control short-term dynamics at the synapse. Inactivation during brief, repetitive stimulation is primarily attributed to closed-state inactivation, and several factors modulate the susceptibility of voltage-gated calcium channels to this form of inactivation. We show that alternative splicing of an exon in a cytoplasmic region of the Ca V2.2 channel modulates its sensitivity to inactivation during trains of action potential waveforms. The presence of this exon, exon 18a, protects the Ca V 2.2 channel from entry into closed-state inactivation specifically during short (10 ms to 3 s) and small depolarizations of the membrane potential (؊60 mV to ؊50 mV). The reduced sensitivity to closed-state inactivation within this dynamic range likely underlies the differential responsiveness of Ca V2.2 splice isoforms to trains of action potential waveforms. Regulated alternative splicing of Ca V2.2 represents a possible mechanism for modulating short-term dynamics of synaptic efficacy in different regions of the nervous system. T he Ca V 2 class of voltage-gated calcium channels regulates calcium entry that triggers exocytosis from presynaptic nerve terminals (1). The temporal dynamics of calcium channel responses to action potential trains impact the fidelity of synaptic transmission (2). Membrane depolarization both activates and inactivates voltage-gated calcium channels. With repetitive, brief depolarizations, inactivation of calcium channels accumulates over time and progressively decreases calcium entry.Cumulative inactivation, a feature of both native and cloned Ca V 2 calcium channels, has been studied in detail because of its importance in regulating the short-term dynamics of synaptic efficacy (2-8). Inactivation that accumulates during brief, repetitive stimulation is thought to result from a process known as closed-state inactivation (5, 6). That is, voltage-gated calcium channels undergo inactivation in response to depolarizations that are insufficiently large to open the channel. Open-state inactivation is thought to play only a minor role in cumulative inactivation of Ca V 2 calcium channels during brief stimuli such as action potentials. Even during prolonged depolarizations that favor open-state inactivation, Ca V 2 channels inactivate with relatively slow time courses. Only in the case of Ca V 3 channels that deactivate relatively slowly following action potential repolarization has open-state inactivation been implicated in cumulative inactivation (9-11). Several factors modulate the susceptibility of voltage-gated calcium channels to cumulative inactivation, including channel subtype (6), G protein activation (3), interaction with presynaptic proteins (12, 13), and alternative splicing (10, 11). However, a limited number of studies have investigated the mechanisms by which...

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confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing

Thaler

Gray

Lipscombe

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…140 Finally, alternate splice isoforms lacking exon e19 that encodes part of the II-III linker have been reported for Ca V 2.3 that show increased sensitivity to calcium-dependent current enhancement. 141 C-terminal splicing of exon e37a results in selective targeting to small nociceptive neurons. 142,143 Ca V 2.2 and Ca V 2.3 splice variants containing e18a appear to be both spatially and developmentally regulated, with increasing expression in Ca V 2.2 and decreasing expression in Ca V 2.3 over time.…”

Section: Regulation By Alternate Splicingmentioning

confidence: 99%

“…Increased sensitivity to current-enhancement, no syntaxin 1A mediated changes 141 synaptic proteins, may provide an additional mechanism by which synaptic calcium entry, and thus neurotransmitter release, may be fine-tuned and adapted to specific physiological, and perhaps brain region specific requirements. Surprisingly little is known about how synaptic protein isoforms contribute to calcium channel and exocytotic function through development.…”

Section: Regulation By Alternate Splicingmentioning

confidence: 99%

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

Davies

Zamponi²

2008

Channels

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Alternative Splicing of Neuronal Cav2 Calcium Channels

Lipscombe

Allen

Gray

et al. 2008

Structure, Function, and Modulation of Neuronal Voltagegated Ion Channels

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Alternate Splicing in the Cytosolic II–III Loop and the Carboxy Terminus of Human E-type Voltage-Gated Ca Channels: Electrophysiological Characterization of Isoforms

Cited by 53 publications

References 35 publications

Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing

Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

Alternative Splicing of Neuronal Cav2 Calcium Channels

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Alternate Splicing in the Cytosolic II–III Loop and the Carboxy Terminus of Human E-type Voltage-Gated Ca Channels: Electrophysiological Characterization of Isoforms

Cited by 53 publications

References 35 publications

Cumulative inactivation of N-type CaV2.2 calcium channels modified by alternative splicing

Cumulative inactivation of N-type CaV2.2 calcium channels modified by alternative splicing

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

Alternative Splicing of Neuronal Cav2 Calcium Channels

Contact Info

Product

Resources

About

Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing

Cumulative inactivation of N-type Ca_V2.2 calcium channels modified by alternative splicing