Disturbances in Glucose-Tolerance, Insulin-Release, and Stress-Induced Hyperglycemia upon Disruption of the Cav2.3 (α1E) Subunit of Voltage-Gated Ca2+Channels

Pereverzev, Alexey; Mikhna, M. G.; Vajna, Rolf; Gissel, Cornelia; Henry, Margit; Weiergräber, Marco; Hescheler, Jürgen; Smyth, Neil; Schneider, Toni

doi:10.1210/mend.16.4.0801

Cited by 53 publications

(55 citation statements)

References 53 publications

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“…Finally, we examined the role of R-type VGCCs in the observed regulation using both pharmacological blockade by SNX-482, and by the genetic ablation of the ␣1E channel subunit in mice (31). In both these models, the inhibition of glutamate release by muscimol was abolished.…”

Section: Discussionmentioning

confidence: 99%

“…Preparation of Synaptosomes-Percoll gradient-purified synaptosomes were prepared as described previously (30) from the cerebral cortices of 2-month-old male Sprague-Dawley rats or from male wild-type or R-type (Ca V 2.3) ␣1E subunit-deficient (␣1E Ϫ/Ϫ ) mutant mice characterized previously (31). On incubation at 37°C, synaptosomes show metabolic competence and ability to release neurotransmitters (32,33).…”

Section: Methodsmentioning

confidence: 99%

“…To authenticate the role of R-type VGCCs in the observed modulation of glutamate release by muscimol, we carried out experiments utilizing synaptosomes prepared from the neocortex of ␣1E subunit knock-out (␣1E Ϫ/Ϫ ) mice lacking the R-type VGCC activity (31). In wild-type mice, glutamate release evoked by 1 mM 4AP under control conditions (35.5 Ϯ 1.3 nmol/mg/5 min) was significantly reduced by muscimol (200 M, 31.6 Ϯ 0.4 nmol/mg/5 min, 89% of control release in wildtype mice; Fig.…”

Section: Syn I)mentioning

confidence: 99%

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Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Long

Mercer

Begum

et al. 2009

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Syn I)mentioning

confidence: 99%

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Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Long

Mercer

Begum

et al. 2009

Journal of Biological Chemistry

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“…Furthermore, Ca v 2.3 deficient mice also develop a phenotype related to defects in the endocrine system and to various other functions [7][8][9]. The expression of Ca v 2.3 in heart was reported but is still under discussion.…”

Section: Introductionmentioning

confidence: 99%

Arrhythmia in Isolated Prenatal Hearts after Ablation of the Cav2.3 (α1E) Subunit of Voltage-gated Ca2+ Channels

Pereverzev²,

Liu³

et al. 2004

Cell Physiol Biochem

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A voltage-gated calcium channel containing Ca_v2.3e (α1Ee) as the ion conducting pore has recently been detected in rat heart. Functional evidence for this Ca²⁺ channel to be involved in the regulation of heart beating, besides L- and T-type channels, was derived from murine embryos where the gene for Ca_v1.2 had been ablated. The remaining ”L-type like“ current component was not related to recombinant splice variants of Ca_v1.3 containing channels. As recombinant Ca_v2.3 channels from rat were reported to be weakly dihydropyridine sensitive, the spontaneous activity of the prenatal hearts from Ca_v2.3(-|-) mice was compared to that of Ca_v2.3(+|+) control animals to investigate if Ca_v2.3 could represent such a L-type like Ca²⁺ channel. The spontaneous activity of murine embryonic hearts was recorded by using a multielectrode array. Between day 9.5 p.c. to 12.5 p.c., the beating frequency of isolated embryonic hearts from Ca_v2.3-deficient mice did not differ significantly from control mice but the coefficient of variation within individual episodes was more than four-fold increased in Ca_v2.3-deficient mice indicating arrhythmia. In isolated hearts from wild type mice, arrhythmia was induced by superfusion with a solution containing 200 nM SNX-482, a blocker of some R-type voltage gated Ca²⁺ channels, suggesting that R-type channels containing the splice variant Ca_v2.3e as ion conducting pore stabilize a more regular heart beat in prenatal mice.

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“…Homozygous littermates are regularly interbred with each other and back-bred into C57Bl/6 (for further information on knock out generation see [10, 11]. Mice were kept at 20°C in makrolon type II cages under a 12h light-dark cycle (7: 00 a.m./p.m.)…”

Section: Methodsmentioning

confidence: 99%

Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

Dibué-Adjei

Kamp

Alpdogan³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Ca_v2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Ca_v2.3-deficient mice and controls on KA-induced seizures. Methods: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). Results: Ablation of Ca_v2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Ca_v2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Ca_v2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Ca_v2.3-defcient mice. Conclusion: These findings give first in vivo evidence for an essential role for Ca_v2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Ca_v2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice.

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Disturbances in Glucose-Tolerance, Insulin-Release, and Stress-Induced Hyperglycemia upon Disruption of the Ca_v2.3 (α1E) Subunit of Voltage-Gated Ca²⁺Channels

Cited by 53 publications

References 53 publications

Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Arrhythmia in Isolated Prenatal Hearts after Ablation of the Ca<sub>v</sub>2.3 (α1E) Subunit of Voltage-gated Ca<sup>2+</sup> Channels

Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

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