Trafficking of neuronal calcium channels

Weiss, Norbert; Zamponi, Gerald W.

doi:10.1042/ns20160003

Cited by 27 publications

(21 citation statements)

References 194 publications

(229 reference statements)

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“…The C-terminal region of voltage-gated calcium channels is implicated in several regulatory aspects including modulation by calcium, phosphorylation, and synaptic proteins [23–26]. Here, we demonstrate that the C-terminus of Ca v 3.3 is an essential structural determinant that contributes to several gating aspects of the channel.…”

Section: Discussionmentioning

confidence: 65%

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

et al. 2019

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The physiological functions controlled by T-type channels are intrinsically dependent on their gating properties, and alteration of T-type channel activity is linked to several human disorders. Therefore, it is essential to develop a clear understanding of the structural determinants responsible for the unique gating features of T-type channels. Here, we have investigated the specific role of the carboxy terminal region by creating a series a deletion constructs expressed in tsA-201 cells and analyzing them by patch clamp electrophysiology. Our data reveal that the proximal region of the carboxy terminus contains a structural determinant essential for shaping several gating aspects of Ca v 3.3 channels, including voltage-dependence of activation and inactivation, inactivation kinetics, and coupling between the voltage sensing and the pore opening of the channel. Altogether, our data are consistent with a model in which the carboxy terminus stabilizes the channel in a closed state.

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Section: Discussionmentioning

confidence: 65%

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

et al. 2019

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“…Trafficking and regulation of Cav2.1 is affected by accessory α 2 δ and β subunits, which affect expression levels, ER exit, and surface localization of the pore-forming Cav subunit [36, 37]. To determine if these accessory subunits impact AnkB regulation of overall and surface Cav2.1 expression levels, we performed surface biotinylation on HEK293T expressing AnkB, Cav2.1 as well as α 2 δ 1 and β 4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ankyrin B and Ankyrin B variants differentially modulate intracellular and surface Cav2.1 levels

et al. 2019

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Ankyrin B (AnkB) is an adaptor and scaffold for motor proteins and various ion channels that is ubiquitously expressed, including in the brain. AnkB has been associated with neurological disorders such as epilepsy and autism spectrum disorder, but understanding of the underlying mechanisms is limited. Cav2.1, the pore-forming subunit of P/Q type voltage gated calcium channels, is a known interactor of AnkB and plays a crucial role in neuronal function. Here we report that wildtype AnkB increased overall Cav2.1 levels without impacting surface Cav2.1 levels in HEK293T cells. An AnkB variant, p.S646F, which we recently discovered to be associated with seizures, further increased overall Cav2.1 levels, again with no impact on surface Cav2.1 levels. AnkB p.Q879R, on the other hand, increased surface Cav2.1 levels in the presence of accessory subunits α 2 δ 1 and β 4. Additionally, AnkB p.E1458G decreased surface Cav2.1 irrespective of the presence of accessory subunits. In addition, we found that partial deletion of AnkB in cortex resulted in a decrease in overall Cav2.1 levels, with no change to the levels of Cav2.1 detected in synaptosome fractions. Our work suggests that depending on the particular variant, AnkB regulates intracellular and surface Cav2.1. Notably, expression of the AnkB variant associated with seizure (AnkB p.S646F) caused further increase in intracellular Cav2.1 levels above that of even wildtype AnkB. These novel findings have important implications for understanding the role of AnkB and Cav2.1 in the regulation of neuronal function in health and disease.

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“…The molecular determinants underlying calcium channel trafficking to and from the plasma membrane is well summarized in [1]. In particular, the α 2 δ subunits of VGCC are traditionally considered to be auxiliary subunits that regulates VGCC trafficking to the plasma membrane [2,3] Pharmacologically, it has been established that Gabapentin (GBP) [4][5][6][7][8] is a ligand of the α 2 δ auxiliary subunits [9], and the α 2 δ-1-bound GBP is able to disrupt VGCC trafficking [10].…”

Section: Introductionmentioning

confidence: 99%

Calcium Channel Trafficking Blocker Gabapentin Bound to the α2δ-1 Subunit of Voltage-Gated Calcium Channel: A Computational Structural Investigation

Li¹

2020

Preprint

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For voltage-gated Ca2+ channel (VGCC), its α2δ subunits are traditionally considered to be auxiliary subunits that regulates VGCC trafficking to the plasma membrane. The antiepileptic, antinociceptive and anxiolytic gabapentin (GBP) has previously been shown to bind the VGCC α2δ subunits with high affinity to disrupt VGCC trafficking. Yet, the interaction between GBP and α2δ still remains poorly understood from a structural point of view. For instance, it is not clear yet what the structural implication is of α2δ-1-bound GBP against VGCC trafficking. With a set of experimental data-driven structural analysis of the VGCC α2δ-1 and its ligand GBP, this article postulates for the first time that: 1), α2δ-1 bound GBP stabilizes the α2δ-1-GBP complex structure; 2), α2δ-1 bound GBP restrains the conformational flexibility of α2δ-1; 3), α2δ-1-bound GBP establishes an electrostatic axis consisting of Q535 (Gln535)-R241 (Arg241)-GBP (gabapentin)-D452 (Asp452), which constitutes an energetically favourable contribution towards the structural stability of the α2δ-1-GBP complex and helps restrains the conformational flexibility and local structural rigidification of α2δ-1; and 4), GBP-induced local conformational inflexibility and structural rigidification of α2δ-1 is one key step in the pharmacological disruption of VGCC trafficking by GBP.

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Trafficking of neuronal calcium channels

Cited by 27 publications

References 194 publications

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

Ankyrin B and Ankyrin B variants differentially modulate intracellular and surface Cav2.1 levels

Calcium Channel Trafficking Blocker Gabapentin Bound to the α2δ-1 Subunit of Voltage-Gated Calcium Channel: A Computational Structural Investigation

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Trafficking of neuronal calcium channels

Cited by 27 publications

References 194 publications

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

Ankyrin B and Ankyrin B variants differentially modulate intracellular and surface Cav2.1 levels

Calcium Channel Trafficking Blocker Gabapentin Bound to the &alpha;2&delta;-1 Subunit of Voltage-Gated Calcium Channel: A Computational Structural Investigation

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Calcium Channel Trafficking Blocker Gabapentin Bound to the α2δ-1 Subunit of Voltage-Gated Calcium Channel: A Computational Structural Investigation