α2δ expression sets presynaptic calcium channel abundance and release probability

Hoppa, Michael B.; Lana, Beatrice; Margas, Wojciech; Dolphin, Annette C.; Ryan, Timothy A.

doi:10.1038/nature11033

Cited by 344 publications

(393 citation statements)

References 35 publications

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“…Pointedly, the selectivity preferences are opposite for each respective study, suggesting that there may be cell-specific preferences for Ca V 2 subtype expression, or that selective expression (displacement) depends on different factors at the cell body and the synapse. Interestingly, Hoppa et al 20 confirmed that Ca V 2.1 overexpression in hippocampal neurons did not cause displace Ca V 2.2 channels at the synapse, but did lead to increased current density at the cell body, a finding that mirrors what we report in sympathetic neurons here, lending support to the idea that similar mechanisms are in play in both neuronal subtypes, but with strikingly different outcomes in the two cellular compartments.…”

Section: Discussionsupporting

confidence: 77%

“…The auxiliary subunit a 2 d created a "bottleneck" or limitation in Ca V 2 localization to the presynapse, 20 so it is interesting that we found a Ca V 2 selectivity preference based on various a 2 ds. Though it is not explicitly demonstrated, it is possible that a 2 ds are not only the limiting factor in presynaptic membrane localization, but also the mechanism by which selectivity is conferred for presynaptic Ca V 2 subtype expression.…”

Section: Discussionmentioning

confidence: 94%

“…Many expression and trafficking studies regarding Ca V 2 channels have been limited to presynaptic expression 17,19, . 20 With many presynaptic-specific interactions it could be possible that those studies overlooked instances of selectivity between Ca V 2 subtypes that occur outside of the presynapse.…”

Section: Discussionmentioning

confidence: 99%

“…However, clearly specific effects of different a2d subunits were not observed, and effects of distinct a2d subunits on specific expressed Ca V channels were not tested. 20 In this study, the goal was to examine Ca V 2 channel expression on the somatic membrane of rat superior cervical ganglion (SCG) neurons. By examining somatic rather than presynaptic channels, we hoped to reduce the variables as presynaptic trafficking requires more protein interactions.…”

Section: Introductionmentioning

confidence: 99%

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Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits

Scott

Kammermeier

2017

Channels

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Type two voltage gated calcium (Ca V 2) channels are the primary mediators of neurotransmission at neuronal presynapses, but their function at neural soma is also important in regulating excitability. 1 Mechanisms that regulate Ca V 2 channel expression at synapses have been studied extensively, which motivated us to perform similar studies in the soma. Rat sympathetic neurons from the superior cervical ganglion (SCG) natively express Ca V 2.2 and Ca V 2.3. 2 We noted previously that heterologous expression of Ca V 2.1 but not Ca V 2.2 results in increased calcium current in SCG neurons. 3 In the present study, we extended these observations to show that both Ca V 2.1 and Ca V 2.3 expression resulted in increased calcium currents while Ca V 2.2 expression did not. Further, Ca V 2.1 could displace native Ca V 2.2 channels, but Ca V 2.3 expression could not. Heterologous expression of the individual accessory subunits a 2 d-1, a 2 d-2, a 2 d-3, or b4 alone failed to increase current density, suggesting that the calcium current ceiling when Ca V 2.2 was over-expressed was not due to lack of these subunits. Interestingly, introduction of recombinant a2d subunits produced surprising effects on displacement of native Ca V 2.2 by recombinant channels. Both a 2 d-1 and a 2 d-2 seemed to promote Ca V 2.2 displacement by recombinant channel expression, while a 2 d-3 appeared to protect Ca V 2.2 from displacement. Thus, we observe a selective prioritization of Ca V channel functional expression in neurons by specific a 2 d subunits. These data highlight a new function for a 2 d subtypes that could shed light on subtype selectivity of Ca V 2 membrane expression.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits

Scott

Kammermeier

2017

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“…In fact, recent evidence has shown that at many fast transmitting presynaptic terminals, only a small number of VGCCs are closely associated with synaptic vesicles via interactions with AZ proteins. 2,4,6 At many of these synapses, vesicle release appears to be triggered by the spatially localized and largely nonoverlapping single channel-derived cloud of calcium ions (nanodomain) after channel opening. 1,3,7 In addition, since VGCC open probability during a brief action potential (p 0 ) is often low, vesicle release is unreliable.…”

mentioning

confidence: 99%

Single calcium channels stand out in the crowd

Dittrich

Meriney

2016

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The α2δ‐1/NMDA receptor complex is involved in brain injury after intracerebral hemorrhage in mice

Song

Jin

et al. 2021

Ann Clin Transl Neurol

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Background: Intracerebral hemorrhage (ICH), a common cerebrovascular disease, seriously threatens human health and has severe secondary injuries, while existing treatment methods have many limitations. a2d-1 is a subunit of voltage-gated Ca 2+ channels (VGCCs) and can act on glutamate receptor Nmethyl-D-aspartate receptors (NMDARs) to relieve neuropathic pain. Methods: We first performed ICH modeling on WT mice and Cacna2d1 knockout (KO) mice. The expression levels of GluN1 and a2d-1 were measured by Western blot and q-PCR, and the interaction between the two proteins was evaluated by coprecipitation. The neuronal apoptosis was detected by the TUNEL assay, and the expression levels of inflammatory factors were assessed by ELISA. The nerve functions of mice were evaluated using behavioral experiments including corner turn test and forelimb use asymmetry. Cerebral hematoma was indicated by brain water content and lesion volume. Results: ICH up-regulated the expression levels of a2d-1 and GluN1. KO of Cacna2d1 significantly reduced the ICH-induced apoptosis. The treatment of gabapentin on a2d-1 also significantly reduced the occurrence of apoptosis. KO of Cacna2d1 also reduced the ICH-induced levels of inflammatory factors. Furthermore, neural functions were also significantly improved. Conclusion: Cacna2d1 KO alleviates cerebral hematoma in ICH mice, exhibits a significant regulating effect on its secondary injuries such as neuronal apoptosis and inflammation, and restores the nerve functions of ICH mice. Loss of Cacna2d1 can provide useful therapeutic clues for ICH treatment.

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α2δ expression sets presynaptic calcium channel abundance and release probability

Cited by 344 publications

References 35 publications

Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits

Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits

Single calcium channels stand out in the crowd

The α2δ‐1/NMDA receptor complex is involved in brain injury after intracerebral hemorrhage in mice

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α2δ expression sets presynaptic calcium channel abundance and release probability

Cited by 344 publications

References 35 publications

CaV2 channel subtype expression in rat sympathetic neurons is selectively regulated by α2δ subunits

CaV2 channel subtype expression in rat sympathetic neurons is selectively regulated by α2δ subunits

Single calcium channels stand out in the crowd

The α2δ‐1/NMDA receptor complex is involved in brain injury after intracerebral hemorrhage in mice

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Product

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Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits

Ca_V2 channel subtype expression in rat sympathetic neurons is selectively regulated by α₂δ subunits