Regulation of Calcium Channels and Synaptic Function by Auxiliary α2δ Subunits

Dolphin, Annette; Obermair, Gerald J.

doi:10.1007/978-3-031-08881-0_5

Cited by 2 publications

(3 citation statements)

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“…In the present study, the distribution of α 2 δ-1 protein in the spinal cord was clearly determined using immunohistochemistry and imaging analysis. Strong α 2 δ-1-positive signals were detected at the highest density in the superficial layers of the spinal dorsal horn, which are known as the projection sites of the primary afferent fibers 51 , consistent with previous reports 3 8 9 26 .…”

Section: Discussionsupporting

confidence: 92%

“…Voltage-gated calcium channels (VGCCs) consist of four subunits: the pore-forming α 1 subunit and three auxiliary α 2 δ, β, and γ subunits 1 . The α 2 δ subunit has four distinct isoforms (i. e., α 2 δ-1, -2, -3, and -4), with the α 2 δ-1 subunit in particular playing important roles in several neurological disorders 2 3 . For instance, the upregulation of α 2 δ-1 mRNA and protein has been reported in various experimental animal models of neuropathic pain 4 5 6 7 8 9 10 11 12 13 14 15 , anxiety 16 , and epilepsy 17 .…”

Section: Introductionmentioning

confidence: 99%

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The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation

et al. 2022

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Gabapentinoids are specific ligands for the α2δ-1 subunit of voltage-gated calcium channels. This class of drugs, including gabapentin and pregabalin, exert various pharmacological effects and are widely used for the treatment of epilepsy, anxiety, and chronic pain. The mechanism of action of gabapentinoids involves both direct modulation of calcium channel kinetics and inhibition of channel trafficking and expression, which contribute to the above pharmacological effects. In the present study, we investigated the effects of mirogabalin, a novel potent gabapentinoid, on expression levels of the α2δ-1 subunit in the spinal dorsal horn in a rat model of spinal nerve ligation (SNL) as an experimental animal model for peripheral neuropathic pain. The neuropathic pain state was induced by SNL in male Sprague – Dawley rats. After the development of mechanical hypersensitivity, the animals received 10 mg/kg mirogabalin or vehicle orally for 5 consecutive days and were subjected to immunohistochemical analysis of α2δ-1 subunit expression in the spinal cord. In the SNL model rats, expression of the α2δ-1 subunit significantly increased in the spinal dorsal horn at the ipsilateral side of nerve injury, while mirogabalin inhibited this increase. In conclusion, the α2δ-1 subunit was upregulated in the spinal dorsal horn of SNL model rats, and repeated administration of mirogabalin inhibited this upregulation. The inhibitory effect of mirogabalin on upregulation of the α2δ-1 subunit after nerve injury is considered to contribute to its analgesic effects in peripheral neuropathic pain.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation

et al. 2022

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“…This is particularly relevant in the context of genetic manipulations of one of the two paired neurons: as one of the paired neurons can be genetically modified by overexpression or knockdown of specific proteins, bi-directional stimulation protocols allow analyzing pre- and post-synaptic consequences in comparison with wild-type synaptic connections in the same neuronal network. As a proof of principle, we altered the expression of α 2 δ proteins, which act, on the one hand, as auxiliary subunits of voltage-gated calcium channels ( Geisler et al, 2015; Ablinger et al, 2020 ; Dolphin and Obermair, 2022 ), and on the other hand as critical synaptic organizers ( Eroglu et al, 2009 ; Geisler et al, 2019 ; Schöpf et al, 2021 ; Ablinger et al, 2022 ). Hence, we employed cultured paired hippocampal neurons to investigate the role of a splice variant of the α 2 δ-2 isoform in the trans-synaptic regulation of synapse formation and synaptic transmission, including short-term synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

An ex vivo Model of Paired Cultured Hippocampal Neurons for Bi-directionally Studying Synaptic Transmission and Plasticity

Stanika¹,

Obermair²

2023

BIO-PROTOCOL

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Synapses provide the main route of signal transduction within neuronal networks. Many factors regulate critical synaptic functions. These include presynaptic calcium channels, triggering neurotransmitter release, and postsynaptic ionotropic receptors, mediating excitatory and inhibitory postsynaptic potentials. The key features of synaptic transmission and plasticity can be studied in primary cultured hippocampal neurons. Here, we describe a protocol for the preparation and electrophysiological analysis of paired hippocampal neurons. This model system allows the selective genetic manipulation of one neuron in a simple neuronal network formed by only two hippocampal neurons. Bi-directionally analyzing synaptic transmission and short-term synaptic plasticity allows the analysis of both pre- and postsynaptic effects on synaptic transmission. For example, with one single paired network synaptic responses induced by both, a wild-type neuron and a genetically modified neuron can be directly compared. Ultimately, this protocol allows experimental modulation and hence investigation of synaptic mechanisms and thereby improves previously developed methods of studying synaptic transmission and plasticity in ex vivo cultured neurons. Key features Preparation of ex vivo paired cultured hippocampal neurons. Bi-directional electrophysiological recordings of synaptic transmission and plasticity. Genetic modulation of synaptic network formation (demonstrated by presynaptic viral overexpression of the auxiliary calcium channel α 2 δ-2 subunit). Graphical overview

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Regulation of Calcium Channels and Synaptic Function by Auxiliary α2δ Subunits

Cited by 2 publications

References 154 publications

The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation

The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation

An ex vivo Model of Paired Cultured Hippocampal Neurons for Bi-directionally Studying Synaptic Transmission and Plasticity

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