Structural and functional differences between L-type calcium channels: crucial issues for future selective targeting

Zuccotti, Annalisa; Clementi, Stefano; Reinbothe, Thomas; Torrente, Angelo G.; Vandael, David; Pirone, Antonella

doi:10.1016/j.tips.2011.02.012

Cited by 72 publications

(74 citation statements)

References 93 publications

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“…However, besides peripheral immune cells, brain endothelial cells of the blood-brain-barrier (BBB) as well as CNS-resident microglia contribute to inflammation and axonal damage [39]. As it is known that α 2 δ auxiliary subunits are widely expressed [40], we systemically checked the mRNA expression of the pregabalin-sensitive α 2 δ auxiliary subunits, α 2 δ-1 (gene: Cacna2d1) and α 2 δ-2 (gene: Cacna2d2), as well as functional pregabalin effects in different cell types known to be relevant in MS/EAE pathophysiology.…”

Section: Diverse Cell Types Relevant In Eae Show No Response To Pregamentioning

confidence: 99%

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Hundehege¹,

Fernández‐Orth²,

Römer³

et al. 2018

Neurosignals

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Background/Aims: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca²⁺ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. Results: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca²⁺ levels in EAE lesions. Conclusion: The presented data suggest that pregabalin primarily acts on neuronal Ca²⁺ channel trafficking thereby reducing Ca²⁺-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases.

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Section: Diverse Cell Types Relevant In Eae Show No Response To Pregamentioning

confidence: 99%

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Hundehege¹,

Fernández‐Orth²,

Römer³

et al. 2018

Neurosignals

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Section: Ltcc Effect Of Oxadiazolo[34-c][14]thiazinonesmentioning

confidence: 99%

“…In particular, LTCC may be the target for various diseases, ranging from central nervous system (CNS) diseases [19] to cancer [20]. It is known that LTCC belong to the Ca v 1 family, that includes four isoforms [19]: Ca v 1.1eCa v 1.4; these modulate various functions and are expressed in several organs and tissues. The binding-sites of 1,4-dihydropyridines and phenylalkylamines at the calcium channel a 1 subunit have been largely characterized [19], more than the benzothiazepines binding site.…”

Section: Ltcc Effect Of Oxadiazolo[34-c][14]thiazinonesmentioning

confidence: 99%

Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones

Carosati

Ioan

Barrano

et al. 2015

European Journal of Medicinal Chemistry

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“…Voltage-gated Ca 2+ channels can be divided into L-type, P/Qtype, N-type, R-type, and T-type. 25 Voltage-gated L-type Ca 2+ channels (LTCCs) are activated by membrane depolarization, and serve as the principal route of Ca 2+ entry in electrically excitable cells such as neurons and muscle. 26,27 Our study 28 provided the first evidence that the opening of plasma membrane LTCCs by the corresponding selective agonist FPL-64176 29 produces robust vomiting both in terms of its frequency and the percentage of animals vomiting.…”

Section: +mentioning

confidence: 99%

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

Darmani

Zhong²

2015

Gastro Open J

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Citation-ATPase inhibitor) cause vomiting in the least shrew, whereas blockade of LTCC by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic activity against diverse emetogens including agonists of 5-HT 3 (e.g. 5-HT or 2-Me-5-HT)-, NK 1 (GR73632)-, D 2 (apomorphine or quinpirole)-, and M 1 (McN-A343)-receptors, but can also potentiate the antiemetic efficacy of well-established antiemetic palonosetron against the non-specific emetogen, cisplatin. The transmission of emesis signals in the gastrointestinal tract and brainstem is crucially dependent on Ca 2+ channels in neurons. In this review, we will examine the current knowledge on the role of Ca 2+ channels and Ca 2+-dependent signaling pathways in the perception and modulation of emesis.

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Structural and functional differences between L-type calcium channels: crucial issues for future selective targeting

Cited by 72 publications

References 93 publications

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones

Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

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