Subunits of purified calcium channels. Alpha 2 and delta are encoded by the same gene.

Jongh, Karen S. De; Warner, Concepcion; Catterall, William A.

doi:10.1016/s0021-9258(18)77174-3

Cited by 257 publications

(29 citation statements)

References 34 publications

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“…The two polypeptides (α2 and δ) making up the auxiliary α2δ subunit are encoded by the same gene, of which there are four (CACNA2D1-4) (for review see 34 ). The gene product encodes a pre-protein, which is proteolytically processed into α2 and δ 35,36 .…”

Section: [H1] Auxiliary Cav Subunitsmentioning

confidence: 99%

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

2020

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Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of neurotransmitters. Voltage-gated Ca 2+ (Cav) channels play a pivotal role in this process as they are the major conduits for the Ca 2+ ions that trigger the fusion of neurotransmitter-containing vesicles with the presynaptic membrane. Alterations in the intrinsic function of these channels, and their positioning within the active zone can profoundly alter the timing and strength of synaptic output. Advances in optical and electron microscopic imaging, structural biology and molecular techniques have facilitated recent breakthroughs in our understanding of the properties of Cav channels that support their presynaptic functions. Here we examine the nature of these channels, how they are trafficked to and anchored within presynaptic boutons, and the mechanisms that allow them to function optimally in shaping the flow of information through neural circuits.

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Section: [H1] Auxiliary Cav Subunitsmentioning

confidence: 99%

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

2020

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“…To date, four α 2 δ isoforms (α 2 δ 1 -α 2 δ 4 ), encoded by the CACNA2D1-CACNA2D4 genes, have been identified [13,14]. Being transcribed from a single gene [59], the α 2 δ protein undergoes post-translational proteolytic cleavage into α 2 and δ polypeptides [60] that remain linked via disulfide bonds [61]. Although it is generally assumed that every α 2 δ isoform can associate with any HVA α 1 pore-forming subunit, recent findings suggest distinct α 1 -preferences for some α 2 δ isoforms [62][63][64][65].…”

Section: α2δ Subunits Are Many-sided Extracellular Interaction Partners Involved In Synaptogenesismentioning

confidence: 99%

More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation

et al. 2021

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Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. However, studies on molecular interaction partners and recent progress in omics technologies have extended the actual concept of these molecules. With this review, we want to illustrate some new perspectives of VGCCs reaching beyond their function as calcium-permeable pores in the plasma membrane. Therefore, we will discuss the relevance of VGCCs as voltage sensors in functional complexes with ryanodine receptors, channel-independent actions of auxiliary VGCC subunits, and provide an insight into how VGCCs even directly participate in gene regulation. Furthermore, we will illustrate how structural changes in the intracellular C-terminus of VGCCs generated by alternative splicing events might not only affect the biophysical channel characteristics but rather determine their molecular environment and downstream signaling pathways.

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“…The proteolytic cleavage site in α2δ-1 has been identified to be between A and V in the sequence LEA~VEME (De Jongh et al, 1990;Jay et al, 1991) (A945 and V946 in the rat sequence used here, Figure 1A), and we have shown that mutation of this site prevents the cleavage of α2δ-1 and abolishes the ability of α2δ-1 to increase calcium channel currents (Kadurin et al, 2016). Initial scrutiny of this sequence suggested a role for matrix metalloprotease (MMP) enzymes, specifically A Disintegrin and Metalloprotease (ADAM)10 or ADAM17/Tumor necrosis factor (TNF)-α converting enzyme (TACE).…”

Section: Sequence Of Cleavage Site In α2δ-1 Predicts Metalloproteases and Adams As Candidate Proteasesmentioning

confidence: 99%

Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α₂δ subunits, and enables calcium current enhancement

Kadurin

Dahimène

Page

et al. 2021

Preprint

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The auxiliary α2δ subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The α2δ proteins are translated as pre-proteins encoding both α2 and δ, and post-translationally proteolysed into α2 and δ subunits, which remain associated as a complex. In this study we have identified ADAM17 as a key protease involved in proteolytic processing of pro-α2δ-1 and α2δ-3 subunits. We provide three lines of evidence: firstly, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Secondly, proteolytic cleavage of both α2δ-1 and α2δ-3 is markedly reduced in cell lines by knockout of ADAM17 but not ADAM10. Thirdly, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature α2δ is essential for the enhancement of CaV function, and in agreement, knockout of ADAM17 inhibited the ability of α2δ-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of α2δ-1 and α2δ-3, and thus a potential drug target in neuropathic pain.

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Subunits of purified calcium channels. Alpha 2 and delta are encoded by the same gene.

Cited by 257 publications

References 34 publications

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation

Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α₂δ subunits, and enables calcium current enhancement

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Subunits of purified calcium channels. Alpha 2 and delta are encoded by the same gene.

Cited by 257 publications

References 34 publications

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release

More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation

Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α2δ subunits, and enables calcium current enhancement

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Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α₂δ subunits, and enables calcium current enhancement