Subunit Architecture and Atomic Structure of Voltage-Gated Ca2+ Channels

Catterall, William A.

doi:10.1007/978-3-031-08881-0_2

Cited by 4 publications

(5 citation statements)

References 91 publications

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“…The abnormal activation of these channels leads to the influx of Ca 2+ into the cell, which plays a critical role in the imbalance of the action potential and finally helps in the triggering and propagation of seizure. Based on the electrophysiological studies, the VGCCs are classified into five different types, i.e., L-, N-, P/Q-, R-, and T-type (Catterall, 2000). The detailed explanation of VGCCs regarding structure, function, types, and role in the pathophysiology of epilepsy has been comprehensively explained by Jie and Feng, as shown in Figure 4A (Xu and Tang, 2018), and Rajakulendran and Michael.…”

Section: Interaction With Voltage Gated Calcium Channelsmentioning

confidence: 99%

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

Waris,

Ullah,

Asim

et al. 2024

Front. Pharmacol.

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Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

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Section: Interaction With Voltage Gated Calcium Channelsmentioning

confidence: 99%

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

Waris,

Ullah,

Asim

et al. 2024

Front. Pharmacol.

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“…199,209,210 However, the location of the recently identified PIP 2 binding site implies a role for PIP 2 in stabilizing the resting state for voltage-sensing domain 2, providing a rationale for PIP 2 effects on voltage properties. 38,41 This site, at the interface of voltage-sensing domain II and pore domain III, makes multiple contacts with the AID helix in Loop I−II (Figure 2A), suggesting a possible allosteric mechanism for PIP2 modulation of Ca V β and Gβγ subunit binding, 209 which might also apply to CRMP2.…”

Section: ■ Future Directionsmentioning

confidence: 99%

“…PIP 2 affects rundown and voltage dependence of Ca V 2.2, voltage-independent inhibition, and also has been shown to prevent inhibition by G-proteins . The picture of PIP 2 and its hydrolysis products in regulation of Ca V channels is complex. ,, However, the location of the recently identified PIP 2 binding site implies a role for PIP 2 in stabilizing the resting state for voltage-sensing domain 2, providing a rationale for PIP 2 effects on voltage properties. , This site, at the interface of voltage-sensing domain II and pore domain III, makes multiple contacts with the AID helix in Loop I–II (Figure A), suggesting a possible allosteric mechanism for PIP2 modulation of Ca V β and Gβγ subunit binding, which might also apply to CRMP2.…”

Section: Future Directionsmentioning

confidence: 99%

Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief

Perez-Miller,

Gomez,

Khanna

2024

ACS Pharmacol. Transl. Sci.

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Ion channels serve pleiotropic functions. Often found in complexes, their activities and functions are sculpted by auxiliary proteins. We discovered that collapsin response mediator protein 2 (CRMP2) is a binding partner and regulator of the N-type voltage-gated calcium channel (Ca V 2.2), a genetically validated contributor to chronic pain. Herein, we trace the discovery of a new peptidomimetic modulator of this interaction, starting from the identification and development of CBD3, a CRMP2-derived Ca V binding domain peptide. CBD3 uncouples CRMP2−Ca V 2.2 binding to decrease Ca V 2.2 surface localization and calcium currents. These changes occur at presynaptic sites of nociceptive neurons and indeed, CBD3 ameliorates chronic pain in preclinical models. In pursuit of a CBD3 peptidomimetic, we exploited a unique approach to identify a dipeptide with low conformational flexibility and high solvent accessibility that anchors binding to Ca V 2.2. From a pharmacophore screen, we obtained CBD3063, a small-molecule that recapitulated CBD3's activity, reversing nociceptive behaviors in rodents of both sexes without sensory, affective, or cognitive effects. By disrupting the CRMP2−Ca V 2.2 interaction, CBD3063 exerts these effects indirectly through modulating Ca V 2.2 trafficking, supporting CRMP2 as an auxiliary subunit of Ca V 2.2. The parent peptide CBD3 was also found by us and others to have neuroprotective properties at postsynaptic sites, through N-methyl-D-aspartate receptor and plasmalemmal Na + /Ca 2+ exchanger 3, potentially acting as an auxiliary subunit for these pathways as well. Our new compound is poised to address several open questions regarding CRMP2's role in regulating the Ca V 2.2 pathways to treat pain with the potential added benefit of neuroprotection.

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“…Voltage-gated Ca 2+ channels are the main pathway of calcium influx and are involved in the intracellular excitatory effect, including six types: L-, N-, P-, Q-, R-, and T-type. [11] There are two categories of them, namely high voltage-activated and low voltage-activated Ca2 + channels. At present, the research on gene mutation of T-type ones in humans is relatively limited compared to mice.…”

Section: Ca 2+ Channelsmentioning

confidence: 99%

The Pathogenesis of Epilepsy and its Diagnosis and Treatment

Jiang¹

2023

HSET

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Epilepsy is one of the most prevalent, chronic, and severe seizure-related disorder of the nervous system, affecting seventy million individuals globally. The risk factors and pathogenesis of epilepsy are also diverse. Nevertheless, there have been mature treatments for epilepsy, among which antiepileptic drug treatment is the most common treatment around the world. Almost 70% of patients have their seizures controlled after drug treatment, but some drug-resistant epilepsies still need to be treated by some other supplemental treatment. In order to take appropriate treatments, we must first fully understand the pathogenesis of epilepsy. As a result, this paper introduced three kinds of pathogenesis in detail, namely abnormal ion channels, abnormal neurotransmitters, and abnormal neuroglial cells. In addition, the diagnosis of epilepsy was also introduced. Last but not least, we highly summarized the treatment except for drug treatment, namely surgical treatment and neuromodulation. Furthermore, this paper also proposed a new treatment, CRISPR-Cas9 gene editing technology, that may be used to treat epilepsy in the future.

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Subunit Architecture and Atomic Structure of Voltage-Gated Ca2+ Channels

Cited by 4 publications

References 91 publications

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief

The Pathogenesis of Epilepsy and its Diagnosis and Treatment

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