An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Sun, Ji; Sun, Xiguang; Li, Zhuo; Ma, Dihui; Y, Lv

doi:10.3892/or.2020.7592

Cited by 3 publications

(8 citation statements)

References 28 publications

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“…HEK-293 and PC12 cells for spinocerebellar ataxia type 6 [ 191 ]. SH‑SY5Y cells for progressive myoclonic epilepsy [ 161 ] AAV9-mediated delivery of miR-3191-5p in mice rescued ataxia, motor deficits, and purkinje cell degeneration [ 165 ] MiRNA-3191-5p prevented the hyperacute disease in hyperacute model of spinocerebellar ataxia type 6 mice [ 226 ] SIS-RNAi could rescue spinocerebellar ataxia type 6 [ 160 ] Barbiturate pentobarbital could block Cav2.1 current [ 166 ] Acetazolamide had no effect on HEK cells carrying mutation for episodic ataxia type 2 [ 145 ] Apoptotic pathway in progressive myoclonic epilepsy [ 161 ] Apoptotic pathway in ataxia [ 191 ] CACNA1C Calcium voltage-gated channel subunit alpha1 C Cav1.2 L-type None Human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) for long-QT syndrome phenotype [ 162 ]. Induced pluripotent stem cell (iPSC) knockout resource for autism spectrum disorder [ 163 ].…”

Section: Resultsmentioning

confidence: 99%

“…Apoptotic pathway in progressive myoclonic epilepsy [ 161 ]…”

Section: Resultsmentioning

confidence: 99%

“…Upon intensive review of literature, we found that tsA-201, HEK293T and mouse chromaffin cells are being used to study ID, epilepsy and autism [ 74 , 82 , 84 , 85 ]. Besides, SH-SY5Y human neuroblastoma cells was used for familial hemiplegic migraine type 1 and episodic ataxia [ 159 , 160 ] and progressive myoclonic epilepsy [ 161 ]. Human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) was used for long-QT syndrome phenotype [ 162 ].…”

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

“…Cav1.3 current could be blocked by microRNA-107 [ 188 , 189 ] and amlodipine [ 190 ]. The commonest affected pathway is apoptotic pathway [ 127 , 155 , 161 , 172 , 191 – 196 ] followed by autophagic pathway [ 158 , 197 – 199 ], Ras/Raf/MEK-ERK signaling pathway [ 200 – 203 ] and Wnt pathway [ 173 ]. Further details can be found in Table 3 .…”

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

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Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Section: Resultsmentioning

confidence: 99%

“…Apoptotic pathway in progressive myoclonic epilepsy [ 161 ]…”

Section: Resultsmentioning

confidence: 99%

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

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Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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show abstract

“…Functional analysis in the cell line model (SH-SY5Y neuroblastoma cell line) revealed that CAG repeats of pathogenic expansion in the C-terminus of the CACNA1A gene probably lead to activation of apoptosis factors (Bcl-2/Bax, caspase, and PARP) and induce cell apoptosis in nerve cells. This finding can provide new insights for the treatment of Progressive Myoclonic Epilepsy (PME) [ 21 ]. Ataxia, myoclonus seizures, and progressive cognitive impairment are some features that are usually present in PME patients [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

Alehabib

Esmaeilizadeh

Ranji-Burachaloo

et al. 2021

Orphanet J Rare Dis

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Background Epilepsy is a neurological disorder characterized by the potential to induce seizure and accompanied by cognitive, psychological, and social consequences. CACNA1A gene is a voltage-gated P/Q-type Cav2.1 channel that is broadly expressed in the central nervous system, and the pathogenic variants within this gene may be associated with the epileptic phenotype. In the present study, we collected clinical and molecular data related to epileptic patients with CACNA1A pathogenic variants and investigated possible meaningful relationship between age at onset, neurodevelopmental disorders, type of seizures, brain imaging abnormalities, genotype, and protein domains. Results In our retrospective literature studies, from among 890 articles reviewed, a total of 90 individuals were related to epilepsy phenotype. Our findings showed that about 90 percent of patients have shown the first symptoms in childhood and teenage years and different types of neurodevelopmental disorders, such as intellectual disability, developmental arrest, and behavioral disorders, have been common findings for these patients. Further, a wide range of abnormalities have been observed in their brain imaging, and generalized seizures have been the most type of seizures in these patients. However, our data showed no specific genotype–phenotype correlation in epileptic patients with CACNA1A pathogenic alterations. Conclusions Our study focused on epileptic phenotype in patients with CACNA1A pathogenic variants and showed a wide range of clinical and molecular heterogeneity with no specific genotype–phenotype correlation. It seems that incomplete penetrance, de-novo variants, and modifier genes are obstacles in predicting the clinical outcome.

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Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

Kumari,

Pullaguri,

Rath

et al. 2024

Cancer Drug Resist

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Globally, cancer, as a major public health concern, poses a severe threat to people’s well-being. Advanced and specialized therapies can now cure the majority of people with early-stage cancer. However, emerging resistance to traditional and novel chemotherapeutic drugs remains a serious issue in clinical medicine. Chemoresistance often leads to cancer recurrence, metastasis, and increased mortality, accounting for 90% of chemotherapy failures. Thus, it is important to understand the molecular mechanisms of chemoresistance and find novel therapeutic approaches for cancer treatment. Among the several factors responsible for chemoresistance, calcium (Ca2+) dysregulation plays a significant role in cancer progression and chemoresistance. Therefore, targeting this derailed Ca2+ signalling for cancer therapy has become an emerging research area. Of note, the Ca2+ signal and its proteins are a multifaceted and potent tool by which cells achieve specific outcomes. Depending on cell survival needs, Ca2+ is either upregulated or downregulated in both chemosensitive and chemoresistant cancer cells. Consequently, the appropriate treatment should be selected based on Ca2+ signalling dysregulation. This review discusses the role of Ca2+ in cancer cells and the targeting of Ca2+ channels, pumps, and exchangers. Furthermore, we have emphasised the role of Ca2+ in chemoresistance and therapeutic strategies. In conclusion, targeting Ca2+ signalling is a multifaceted process. Methods such as site-specific drug delivery, target-based drug-designing, and targeting two or more Ca2+ proteins simultaneously may be explored; however, further clinical studies are essential to validate Ca2+ blockers’ anti-cancer efficacy.

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An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Cited by 3 publications

References 28 publications

Calcium channelopathies and intellectual disability: a systematic review

Calcium channelopathies and intellectual disability: a systematic review

Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

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