Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

Kochegarov, Andrei

doi:10.1016/s0143-4160(02)00239-7

Cited by 70 publications

(50 citation statements)

References 133 publications

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“…Increased dorsal horn presynaptic calcium channels can lead to enhanced and/or prolonged presynaptic terminal excitability, resulting in elevated excitatory neurotransmitter release after non-noxious stimulation, which evokes a pain response (tactile allodynia). This hypothesis is supported by the findings that calcium channels are expressed at the presynaptic terminals and involved in excitatory neurotransmitter release (Matthews and Dickenson, 2001;Kochegarov, 2003), nerve injury modulates dorsal horn release of excitatory neurotransmitters (Skilling et al, 1992;Noguchi et al, 1995;Malcangio et al, 2000), and gabapentin, an antihyperalgesic drug that binds to the ␣ 2 ␦-1 subunit, inhibits excitatory neurotransmitter release from presynaptic terminals only in hyperalgesic, but not normal, rat spinal cord and caudal trigeminal nucleus slices (Patel et al, 2000;Maneuf et al, 2001). Colocalization of this subunit with other calcium channelforming subunits in the presynaptic terminals and in vivo electrophysiological studies will provide direct evidences to prove or disprove this hypothesis.…”

Section: Discussionmentioning

confidence: 87%

Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Li¹,

Song²,

Higuera³

et al. 2004

J. Neurosci.

228

202

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Peripheral nerve injury induces upregulation of the calcium channel ␣ 2 ␦-1 structural subunit in dorsal root ganglia (DRG) and dorsal spinal cord of spinal nerve-ligated rats with neuropathic pain, suggesting a role of the calcium channel ␣ 2 ␦-1 subunit in central sensitization. To investigate whether spinal dorsal horn ␣ 2 ␦-1 subunit upregulation derives from increased DRG ␣ 2 ␦-1 subunit and plays a causal role in neuropathic pain development, we examined spinal dorsal horn ␣ 2 ␦-1 subunit expression with or without dorsal rhizotomy in spinal nerve-ligated rats and its correlation with tactile allodynia, a neuropathic pain state defined as reduced thresholds to nonnoxious tactile stimulation. We also examined the effects of intrathecal ␣ 2 ␦-1 antisense oligonucleotides on ␣ 2 ␦-1 subunit expression and neuropathic allodynia in the nerve-ligated rats. Our data indicated that spinal nerve injury resulted in time-dependent ␣ 2 ␦-1 subunit upregulation in the spinal dorsal horn that correlated temporally with neuropathic allodynia development and maintenance. Dorsal rhizotomy diminished basal level expression and blocked injury-induced expression of the spinal dorsal horn ␣ 2 ␦-1 subunit and reversed injury-induced tactile allodynia. In addition, intrathecal ␣ 2 ␦-1 antisense oligonucleotides blocked injury-induced dorsal horn ␣ 2 ␦-1 subunit upregulation and diminished tactile allodynia. These findings indicate that ␣ 2 ␦-1 subunit basal expression occurs presynaptically and postsynaptically in spinal dorsal horn. Nerve injury induces mainly presynaptic ␣ 2 ␦-1 subunit expression that derives from increased ␣ 2 ␦-1 subunit in injured DRG neurons. Thus, changes in presynaptic ␣ 2 ␦-1 subunit expression contribute to injury-induced spinal neuroplasticity and central sensitization that underlies neuropathic pain development and maintenance.

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Section: Discussionmentioning

confidence: 87%

Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Li¹,

Song²,

Higuera³

et al. 2004

J. Neurosci.

228

202

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“…Calcium homeostasis in hair cells and spiral ganglion neurons (SGNs) is maintained by regulatory proteins such as calmodulin and calbindin (e.g., Hansen et al, 2003;Hackney et al, 2005), and by several types of calcium channels (Niedzielski et al, 1997;Morley et al, 1998;Parks, 2000;Lopez et al, 2003). Voltagegated calcium channels (VGCCs) play a key role in calcium entry into neurons and control various calcium-dependent functions, including intracellular signaling and gene expression (Snutch and Reiner, 1992;Fuchs, 1996,Kochegarov, 2003Errington et al, 2005). VGCCs can be divided into two groups: low-voltage activated calcium channels that respond to small (~10 mV) changes in the resting membrane potential, and high-voltage activated calcium channels that require stronger (~30 mV) depolarization to open (Perez-Reyes, 1998;Lacinova et al, 2000;Yunker and McEnery, 2003;Layton et al, 2005;Triggle, 2006).…”

Section: Introductionmentioning

confidence: 99%

Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss

et al. 2007

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Cochlear noise injury is the second most frequent cause of sensorineural hearing loss, after aging. Because calcium dysregulation is a widely recognized contributor to noise injury, we examined the potential of calcium channel blockers to reduce noise-induced hearing loss (NIHL) in mice. We focused on two T-type calcium blockers, trimethadione and ethosuximide, which are anti-epileptics approved by the Food and Drug Administration. Young C57BL/6 mice of either gender were divided into three groups: a 'prevention' group receiving the blocker via drinking water before noise exposure; a 'treatment' group receiving the blocker via drinking water after noise exposure; and controls receiving noise alone. Trimethadione significantly reduced NIHL when applied before noise exposure, as determined by auditory brainstem recording. Both ethosuximide and trimethadione were effective in reducing NIHL when applied after noise exposure. Results were influenced by gender, with males generally receiving greater benefit than females. Quantitation of hair cell and neuronal density suggested that preservation of outer hair cells could account for the observed protection. Immunocytochemistry and RT-PCR suggested that this protection involves direct action of T-type blockers on α1 subunits comprising one or more Ca v 3 calcium channel types in the cochlea. Our findings provide a basis for clinical studies testing T-type calcium blockers both to prevent and treat NIHL.

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“…Control of Ca V trafficking by regulating Ca V α 1 -Ca V β interactions is emerging as an important means of modulating cellular excitability 7 . Ca V channel subtypes are major clinical targets for drugs that treat cardiovascular disease, migraine and pain 19 . Development of compounds that could interfere with the AID-ABP binding interactions might provide new ways to modulate Ca V function in pathological states.…”

mentioning

confidence: 99%

Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain

Petegem

Clark

Chatelain

et al. 2004

Nature

404

492

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Voltage-gated calcium channels (Ca V s) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration 1 . An essential Ca V intracellular protein, the β-subunit (Ca V β)1 ,2 , binds a conserved domain (the α-interaction domain, AID) between transmembrane domains I and II of the pore-forming α 1 subunit 3 and profoundly affects multiple channel properties such as voltagedependent activation 2 , inactivation rates 2 , G-protein modulation 4 , drug sensitivity 5 and cell surface expression 6,7 . Here, we report the high-resolution crystal structures of the Ca V β 2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the β-interaction domain (BID), formed the AID-binding site 3, 8; however, this region is largely buried in the Ca V β core and is unavailable for protein-protein interactions. The structure of the AID-Ca V β 2a complex shows instead that Ca V β 2a engages the AID through an extensive, conserved hydrophobic cleft (named the α-binding pocket, ABP). The ABP-AID interaction positions one end of the Ca V β near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca V inactivation 9,10 . Together, these data suggest that Ca V βs influence Ca V gating by direct modulation of IS6 movement within the channel pore. The 1.97 Å resolution structure of the Ca V β 2a core shows that Ca V βs comprise two wellconserved domains (Fig. 1a). The first, an SH3 fold, contains five antiparallel β-strands (β1-β5), a 3 10 helix (η1), and two α-helices (α1 and α2) that lie amino-terminal to β1 and carboxy-terminal to β4, respectively. The strand that completes the SH3 fold, β5 (residues 217-224), is separated in the primary structure from the core of the SH3 domain by approximately 70 residues (variable domain 2, V2, a site of splice variation and amino acid insertions and deletions2) that are absent from the structure (Fig. 1b). The second conserved domain consists of a five-stranded parallel β-sheet (β6-β10), surrounded by six α-helices (α3-α8) and two 3 10 helices (η2 and η3), and is related to the core of nucleotide kinase enzymes.Ca V βs share structural features with membrane-associated guanylate kinases (MAGUKs), a protein scaffold family that organizes signalling components near membranes 11 Comparison of Ca V β 2a with a representative MAGUK, 13), reveals other differences. Superposition of the nucleotide kinase domains shows that the relative orientations of the SH3 and nucleotide kinase domains differ by approximately 90°, an arrangement that makes Ca V β 2a a more elongated structure (Fig. 2a). The nucleotide kinase domain of MAGUKs is homologous to guanylate kinases and retains guanosine monophosphate (GMP) binding, but key residues for enzymatic function are missing 12 . The four-stranded β-sheet nucleotide kinase subdomain that binds GMP in MAGUKs is absent in Ca v β 2a (Fig. 2a). Furthermore, two Ca V β 2a loops (b...

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Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

Cited by 70 publications

References 133 publications

Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss

Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain

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Pharmacological modulators of voltage-gated calcium channels and their therapeutical application

Cited by 70 publications

References 133 publications

Spinal Dorsal Horn Calcium Channel α2δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Spinal Dorsal Horn Calcium Channel α2δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss

Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain

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Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia

Spinal Dorsal Horn Calcium Channel α₂δ-1 Subunit Upregulation Contributes to Peripheral Nerve Injury-Induced Tactile Allodynia