Dataset Information

Anoctamin 3: A Possible Link between Cluster Headache and Ca2+ Signaling.

ABSTRACT: Cluster headache is a severe primary headache characterized by extremely painful attacks of unilateral headache. Verapamil is commonly used as a prophylactic treatment with good effect. In order to search for new pathways involved in the pathophysiology of cluster headache, we analyzed genetic variants that were previously linked to verapamil response in migraine in a Swedish cluster headache case-control sample. We used TaqMan qPCR for genetic screening and performed a gene expression analysis on associated genes in patient-derived fibroblasts, and further investigated which reference genes were suitable for analysis in fibroblasts from cluster headache patients. We discovered a significant association between anoctamin 3, a gene encoding a calcium-activated ion channel, and cluster headache. The association was not dependent on verapamil treatment since the associated variant, rs1531394, was also overrepresented in patients not using verapamil. No difference was found in the anoctamin 3 gene expression between controls and patients. Also, we determined that TBP, IPO8 and PDHB were suitable reference genes in cluster headache fibroblasts. This finding is the first report of an association between a variant in a gene encoding an ion-channel and cluster headache, and the first significant genetic evidence of calcium involvement in cluster headache pathophysiology.

SUBMITTER: Ran C

PROVIDER: S-EPMC6721385 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Anoctamin 3: A Possible Link between Cluster Headache and Ca<sup>2+</sup> Signaling.

Ran Caroline C Fourier Carmen C Arafa Donia D Liesecke Franziska F Sjöstrand Christina C Waldenlind Elisabet E Steinberg Anna A Belin Andrea Carmine AC

Brain sciences 20190730 8

Cluster headache is a severe primary headache characterized by extremely painful attacks of unilateral headache. Verapamil is commonly used as a prophylactic treatment with good effect. In order to search for new pathways involved in the pathophysiology of cluster headache, we analyzed genetic variants that were previously linked to verapamil response in migraine in a Swedish cluster headache case-control sample. We used TaqMan qPCR for genetic screening and performed a gene expression analysis ...[more]

PMID: 31366133

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Project description:Background:Cluster headache (CH) is considered to be a catastrophic disease presenting the most severe human pain condition. Available pharmacological treatments are hampered by unwanted side effects, and there is an urgent need for non-pharmacological treatment alternatives. We present a novel therapeutic approach for chronic CH, having evolved from an episodic CH, using a non-invasive percutaneous bioelectric current stimulation (PBCS), which generates static electric fields in the range of the naturally occurring electric potentials. Patients and Methods:This study employed a retrospective data analysis of 20 cases of chronic cluster headache (CCH) patients, four of those having had cluster-related surgery (SPG, ONS). All patients were treated with PBCS between 2014 and 2018. Data of these patients were analyzed with respect to frequency of CH attacks and triptan application and followed up for one (20 cases) or two (12 cases) years. Results:Four weeks after the first PBCS treatment, cluster headache attacks were reduced from 2.8 to 1.7 per day and triptan application decreased from 2.5 to 1.5 times/day. Six non-responders, 4 of which had pre-CH surgery, did not show any reaction to PBCS, while 14 responders improved within 4 weeks from 2.2 to 0.7 attacks/day and 2.0 to 0.4 triptan applications/day. A 50% or greater reduction of attack frequency was observed in 10 patients after 4 weeks and in 11 patients after 12 weeks. One year after the first treatment, 13/20 patients experienced a reduction of attack frequency of 50% or more, while remarkably 10 patients were completely free of attack. After 2 years, 8 of 12 patients experienced a reduction of attack frequency of 50% or more and 7 of those were completely symptom-free. No serious adverse effects were observed. Conclusion:PBCS is a promising transformative treatment approach for CCH patients. Drug consumption was reduced significantly, and the CCH may revert back to an episodic cluster headache with increasingly long times of remission. Responders can be clearly differentiated from non-responders. The data support the need for randomized controlled trials.

Project description:Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.

Dataset Information

Anoctamin 3: A Possible Link between Cluster Headache and Ca2+ Signaling.

Publications

Anoctamin 3: A Possible Link between Cluster Headache and Ca<sup>2+</sup> Signaling.

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