Background We compared the tolerability and efficacy of erenumab, a monoclonal antibody binding to the calcitonin gene-related peptide receptor, to topiramate for migraine prophylaxis in adults. Methods HER-MES was a 24-week, randomised, double-blind, double-dummy, controlled trial conducted in 82 sites in Germany. Patients with ≥4 migraine days per month and naïve to study drugs were randomly assigned (1:1) to either subcutaneous erenumab (70 or 140 mg/month) plus topiramate placebo (erenumab group) or oral topiramate at the individual dose with optimal efficacy (50–100 mg/day) plus erenumab placebo (topiramate group). The primary endpoint was medication discontinuation due to an adverse event during the double-blind phase. The proportion of patients that achieved ≥50% reduction from baseline in monthly migraine days during the last 3 months of the double-blind phase was a secondary endpoint. Results Seven hundred and seventy-seven patients were randomised (from 22 February 2019 to 29 July, 2020) and 95.1% completed the study. In the erenumab group, 10.6% discontinued medication due to adverse events compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence interval 0.13–0.27; p < 0.001). Significantly more patients achieved a ≥50% reduction in monthly migraine days from baseline with erenumab (55.4% vs. 31.2%; odds ratio 2.76; 95% confidence interval 2.06–3.71; p < 0.001). No new safety signals occurred. Conclusions Erenumab demonstrated a favourable tolerability and efficacy profile compared to topiramate. Trial registration: ClinicalTrials.gov NCT03828539, URL: https://clinicaltrials.gov/ct2/show/NCT03828539

VAMP8 is associated with the recycling endosome compartment rather than with cytotoxic granules and is required for a fusion step between recycling endosomes and the plasma membrane that brings syntaxin-11 to the immune synapse for cytotoxic granule exocytosis.

Allosteric modulators have been identified for several G protein-coupled receptors, most notably muscarinic receptors. To study their mechanism of action, we made use of a recently developed technique to generate fluorescence resonance energy transfer (FRET)-based sensors to monitor G protein-coupled receptor activation. Cyan fluorescent protein was fused to the C terminus of the M 2 muscarinic receptor, and a specific binding sequence for the small fluorescent compound fluorescein arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH. We then measured FRET between the donor cyan fluorescent protein and the acceptor FlAsH in intact cells and monitored its changes in real time. Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes. Removal of the agonists or addition of an antagonist caused a reversal of this signal with rate constants between 400 and 1100 ms. The allosteric ligands gallamine and dimethyl-W84 caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors. The kinetics of these effects were very rapid, with rate constants of 80 -100 ms and ≈200 ms for saturating concentrations of gallamine and dimethyl-W84, respectively. Because these speeds are significantly faster than the responses to antagonists, these data indicate that gallamine and dimethyl-W84 are allosteric ligands and actively induce a conformation of the M 2 receptor with a reduced affinity for its agonists.

In order to fuse lytic granules (LGs) with the plasma membrane at the immunological synapse, cytotoxic T lymphocytes (CTLs) have to render these LGs fusioncompetent through the priming process. In secretory tissues such as brain and neuroendocrine glands, this process is mediated by members of the Munc13 protein family. In human CTLs, mutations in the Munc13-4 gene cause a severe loss in killing efficiency, resulting in familial hemophagocytic lymphohistiocytosis type 3, suggesting a similar role of other Munc13 isoforms in the immune system. Here, we investigate the contribution of different Munc13 isoforms to the priming process of murine CTLs at both the mRNA and protein level. We demonstrate that Munc13-1 and Munc13-4 are the only Munc13 isoforms present in mouse CTLs. Both isoforms rescue the drastical secretion defect of CTLs derived from Munc13-4-deficient Jinx mice. Mobility studies using total internal reflection fluorescence microscopy indicate that Munc13-4 and Munc13-1 are responsible for the priming process of LGs. Furthermore, the domains of the Munc13 protein, which is responsible for functional fusion, could be identified. We conclude from these data that both isoforms of the Munc13 family, Munc13-1 and Munc13-4, are functionally redundant in murine CTLs.

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