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Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthritis, calcium pyrophosphate deposition disease, and the therapies used to treat them, particularly disease-modifying antirheumatic drugs, exemplify clinical contexts where calcium homeostasis has underappreciated relevance. Calcium balance is central to skeletal integrity, immune signalling, and multisystem function in rheumatic diseases, yet it is frequently overshadowed by inflammatory priorities. Despite growing evidence linking calcium disorders to morbidity, integration into routine rheumatology care remains limited, representing a persistent clinical gap. The objective of this review is to synthesize current knowledge on the spectrum, mechanisms, manifestations, and management of calcium disorders in rheumatic diseases. A narrative review was conducted using PubMed, Scopus, and Web of Science, covering literature published between 2015 and 2025, including original studies and reviews. Chronic inflammation, therapeutic exposures, endocrine disruption, and renal involvement collectively drive hypocalcemia, hypercalcemia, secondary hyperparathyroidism, and crystal deposition disorders. These abnormalities contribute to skeletal fragility, renal complications, cardiovascular calcification, and diagnostic uncertainty. Integrating calcium assessment into rheumatologic practice has important implications for risk stratification, individualized therapy, and the prevention of long-term complications. Calcium disorders should be recognized as integral components of rheumatic disease biology rather than incidental comorbidities. The systematic, multidisciplinary integration of calcium homeostasis into rheumatology care can meaningfully improve patient outcomes.

Anticoagulant therapy with dihydroxycoumarin derivatives (DD) is often related to local bleeding during oral surgery. The purpose of this study was to determine whether 3D Bond® (Augma Biomaterials, Katzir, Israel), a biphasic calcium sulfate regenerative bone cement, allows for the management of bleeding during and after oral surgery without discontinuation of anticoagulant therapy. The aim of the study was to investigate whether 3D Bond® biphasic calcium sulfate cement is effective in supporting local hemostasis and wound healing in patients using chronic anticoagulant therapy (dihydroxycoumarin derivatives, DD). The study was divided into a control group and a study group. Disorders of plasma coagulation parameters were confirmed in both groups one day prior to surgery by a standard international normalized ratio (INR) test. The control group consisted of 20 patients with cardiovascular diagnoses who were discontinued on their anticoagulation therapy before extractions of erupted teeth, impacted teeth, and roots. In the study group, 20 patients with various cardiological disorders underwent extractions of erupted teeth, impacted teeth, and roots without anticoagulant treatment discontinuation. 3D Bond® was used topically with a single suture and applied compression in the study group. In the control group, standard collagen sponge compression was utilized. Sutures were removed seven to 10 days after tooth extraction. The visual assessment of bleeding was performed five times within 10 days after surgery. Wound healing and pain following surgery for 10 days were also evaluated in both groups.  Clinical evaluation of the study group revealed no local bleeding in 19 patients (95%) during follow-up. Local bleeding was observed in one patient (5%) at day three; however, it was residual. In the control group, no local bleeding was noted in 16 patients (80%) during follow-up. Local bleeding was observed in four patients (20%) in the control group at day three. All wounds were properly healed, except for the four patients with local bleeding (20%) in the control group.  3D Bond®, which consists of 100% biphasic calcium sulfate bone cement, is effective in inhibiting localized bleeding following oral surgery without requiring discontinuation of dihydroxycoumarin derivative medication. In addition, the clinical effectiveness of 3D Bond® in socket preservation of post-extraction alveolar sockets was observed and is comparable with other biphasic calcium sulfate cements. Many patients are prescribed anticoagulants by their physician as part of their ongoing health management. This often leads to bleeding during and following dental surgery, such as extractions, soft-tissue procedures, and implant-related treatment. Discontinuing or decreasing the patient's anticoagulants poses potential medical risks. Utilization of 3D Bond®, a biphasic calcium sulfate regenerative bone cement, allows management of bleeding during and after those dental procedures that may cause bleeding while continuing the patient on the prescribed anticoagulants.

Background: Nanostructured, rod-shaped microparticles represent a promising drug delivery platform for the pulmonary delivery and targeting of alveolar macrophages by exploiting the aerodynamic advantages of fiber-like geometries. These microrods feature a hierarchical architecture, designed for potential macromolecular payloads, and silica (SiO2)-based systems have previously been shown to successfully deliver oligonucleotides in vitro. However, current microrod systems mainly rely on nanoparticulate SiO2-based frameworks with limited biodegradability and lack a specific escape mechanism to the cytosol. Therefore, a nanostructured calcium phosphate (CaP) framework is proposed as a biodegradable and resorbable alternative, featuring pH-responsive dissolution under endolysosomal conditions. Methods and Results: This study presents the fabrication of nanostructured, rod-shaped calcium phosphate microparticles and discusses their suitability as a potential pulmonary drug delivery platform. The particles feature dissolution-driven disintegration in acidic and ion-rich environments relevant to phagolysosomes. In addition, the particles exhibited a favorable acute cytotoxicity profile in the murine alveolar macrophage cell line MH-S compared with their SiO2-based counterparts. Comparative RNA-seq analysis of MH-S exposed to the particles indicates a mild transcriptomic response, while canonical signatures of classical or alternative macrophage activation programs were not observed, supporting a generally well-tolerated exposure profile of the carrier. Conclusions: Together, these findings establish key prerequisites for employing calcium phosphate microrods as a biodegradable pulmonary carrier platform in subsequent studies incorporating therapeutic cargos.

Calcium pyrophosphate deposition disease (CPPD) is a prevalent cause of inflammatory arthritis in older adults, often complicated by comorbidities that limit standard anti-inflammatory therapies. Despite its burden, evidence for biologic treatments remains limited. Four patients with CPPD, 3 with chronic polyarthritis, and 1 with overlapping gout are presented. All patients were treated with tocilizumab (TCZ) after failure or intolerance to colchicine, non-steroidal anti-inflammatory drugs, or corticosteroids. All patients experienced partial clinical improvement, with reduced inflammation markers and modest reductions in flare frequency or severity. However, corticosteroid dependence persisted in most cases, and the improvement assessment was mostly subjective. Tocilizumab was well tolerated without serious adverse events. Recent reports suggest a potential role for IL-6 blockade in CPPD, yet efficacy remains variable. Comparative studies with Interleukin (IL)-1 inhibitors and emerging data from observational cohorts and pilot trials support further investigation. In conclusion, TCZ may offer clinical benefit in refractory CPPD, while there is a true need for validation in controlled prospective studies. Cite this article as: Bieber A, Tropea A, Brikman S, Palumbo A, Atzeni F. Anti IL-6 treatment for calcium pyrophosphate disease report of 4 cases and a short literature review. Eur J Rheumatol. 2026, 13, 0080, doi: 10.5152/ eurjrheum.2026.25080.

Calcium-ion batteries (CIBs) offer several advantages. CIBs are viable alternatives to lithium-based battery systems owing to the natural abundance, low cost, and high volumetric capacity of calcium. However, their development has been severely constrained by electrolyte instability and water sensitivity. We conducted a systematic examination of Ca(ClO4)2 and Ca(PF6)2 electrolytes, focusing on low-cost salt production, solvent selection, and stringent dehydration procedures. Acetonitrile (ACN) was the ideal solvent for high salt solubility and reversible Ca2+ electrochemistry, while carbonate solvents failed rapidly. We found that even a small amount of moisture in the electrolyte significantly affected the electrochemical performance. This study improved the dehydration process by using 3 Å molecular sieve (MS3A) and vacuum drying to reduce moisture to ppm levels, stabilizing the electrolyte. Prussian blue (PB) half cells exhibited reversible capacities of up to ≈95 mAh g-1, whereas PB-hard carbon full cells utilizing dried Ca(ClO4)2 showed stable cycling over 240 cycles with a Coulombic efficiency of ≈99% and capacity loss of only ≈17%. This study establishes a moisture-controlled electrolyte as a critical enabler for practical CIBs.

MRE11 safeguards genome stability at stalled replication forks, where its activity must be tightly controlled to prevent nascent strand DNA degradation (NSD). However, the upstream signaling mechanisms that limit NSD remain poorly defined. Here, we identify Ser649 (S649) as a previously unrecognized phosphorylation site that limits MRE11 association with stalled forks. We show that S649 phosphorylation is robustly induced by replication stress or elevated cytosolic calcium levels, and is mediated by the calcium-responsive CaMKK2-AMPKα axis in concert with ATR, but independently of CHK1. Loss of S649 phosphorylation enhances MRE11 binding to DNA and increases its association with stalled forks, driving excessive NSD, elevated DNA damage, and increased sensitivity to PARP inhibition. We find that the ATM-mediated S676/S678 phosphorylation primes S649 phosphorylation, which in turn facilitates subsequent phosphorylation of SQ/TQ sites in MRE11. Moreover, we find that CaMKK2-AMPKα activation requires ATR but is independent of ATM. Collectively, our findings reveal a hierarchical signaling mechanism that couples calcium signaling with ATM/ATR pathways to prevent NSD at stalled forks and preserve genome integrity.

Elevated phosphate concentration in proximal tubular fluid promotes calcium phosphate microcrystallopathy, thereby accelerating the progression of chronic kidney disease (CKD). However, the clinical significance of proximal tubular phosphate exposure in humans remains uncertain. We aimed to determine whether estimated proximal tubular fluid phosphate concentration (ePTFp) is independently associated with age-related kidney function decline in adults with and without CKD. We conducted a 5-year prospective cohort study involving 308 adults with and without CKD. ePTFp-a novel, noninvasive index-and serum fibroblast growth factor 23 (FGF23) concentrations were derived from blood and urine measurements. Kidney function decline, expressed as estimated glomerular filtration rate (eGFR) slope, was modeled using linear mixed-effects analysis. Associations of ePTFp and serum FGF23 with eGFR slope were examined using multivariable regression analysis, adjusting for potential covariates at baseline, including age, sex, several comorbidities, current smoking status, eGFR, and urinary glomerular and tubular injury markers. Over 5 years, eGFR declined in participants with and without CKD, with a steeper decline in those with CKD. Higher baseline ePTFp and serum FGF23 were inversely correlated with eGFR slope. In multiple adjusted models, elevated ePTFp remained independently associated with faster eGFR decline, whereas the serum FGF23 association was attenuated after covariate adjustment. Elevated ePTFp was independently linked to accelerated kidney function decline, underscoring the clinical relevance of calcium phosphate microcrystallopathy. ePTFp may represent a practical biomarker with implications for prevention and treatment strategies targeting the aging kidney with proximal tubular phosphate exposure.

Vascular endothelial growth factor (VEGF) is widely used in regenerative medicine and therapeutic research. However, the purification of recombinant VEGF largely relies on affinity chromatography, which requires expensive chromatographic columns, specialized equipment, and multistep processing. These column-based workflows increase operational complexity and cost, particularly for large-scale production. Therefore, the development of an alternative purification strategy to conventional chromatography-based purification for VEGF is needed. In this study, we developed a chromatography-free VEGF purification strategy using an anti-VEGF-scFv-calsequestrin (CSQ) fusion protein that enables calcium-dependent affinity precipitation. The fusion protein retained strong binding affinity for VEGF (Kd = 1.1 nM) while exhibiting rapid and reversible Ca2⁺-dependent polymerization. Upon CaCl₂ addition, the anti-VEGF-scFv-CSQ-VEGF complex rapidly formed aggregates, enabling efficient separation of VEGF from impurities. Using this strategy, VEGF was purified within 30 min with a purity of 94% and a yield of 93%. SEC-HPLC analysis confirmed a purity of 94.3%, and host cell protein contamination was reduced from 1.44 × 104 ppm to 774 ppm. The fusion protein also maintained stable purification performance over five repeated cycles, with VEGF recovery consistently maintained above 85%. These findings demonstrate that the scFv-CSQ fusion protein enables rapid separation of VEGF through calcium-dependent polymerization. This column-free mechanism reduces operational cost and technical complexity, highlighting its potential as an alternative to conventional chromatography-based purification.

The Human cytomegalovirus (HCMV) US21 protein is a calcium-conducting viroporin that modulates intracellular Ca2+ homeostasis, safeguards cells from apoptosis, stimulates cell migration, and supports efficient HCMV replication. To validate pUS21 as a novel target for the identification of antiviral agents, in silico structure-based virtual screening was performed using its predicted structure to identify small molecules capable of engaging the inner part of the pore. Four dihydropyridine compounds (azelnidipine, efonidipine, lercanidipine, and niguldipine) were selected from 249 Calcium Channel Blockers (CCBs) in the DrugBank database. Molecular dynamics simulations of pUS21-ligand complexes predicted that the four selected CCBs formed dynamically stable and low-mobility interactions within the US21 pore, whereas the weak CCB binder felodipine remained highly mobile, supporting the predicted docking-based binding mode. The selected CCBs showed dose-dependent inhibition of HCMV replication in both fibroblasts and endothelial cells, with low micromolar EC50 values. Their antiviral effect was neither cell type- nor strain-dependent, as confirmed against two different clinical isolates, TRwt and VR1814, and was observed to be reduced against a US21-deficient virus, suggesting the specificity of pUS21 as a molecular target. Consistent with the predicted engagement within the pUS21 pore, CCBs prevented pUS21-mediated Ca2+ leakage from the endoplasmic reticulum and impaired both pUS21-induced cell migration and anti-apoptotic activity. Finally, drug combination studies revealed synergistic interactions between CCBs and maribavir treatment. Together, these findings support the hypothesis that clinically used CCBs may target pUS21 viroporin activity and hamper HCMV replication, thus offering a novel and promising antiviral strategy against HCMV, including drug-resistant strains.

The disease course of severe enterovirus (EV) infection with hepatic necrosis is usually fulminant and fatal. Coxsackievirus (CVB3) is the emerging and important serotype of newborn EV inducing hepatic necrosis. Calcium (Ca2+) regulates host immunity, type I interferon (IFN-I), and viral infections. The interaction of Ca2+, IFN-I, and CVB3-induced hepatitis remains to be investigated. To address these issues, we used the Ca2+ blocker manidipine, which reduces Ca2+ influx into cells and is used in the clinic, the human hepatoma cell line (HuH7) for in vitro studies, and a murine infection model. In vitro results showed that CVB3 infection increased levels of intracellular Ca2+ and Ca2+-binding proteins, calmodulin and calcineurin, which are IFN-I suppressors. Moreover, manidipine decreased CVB3 titers in a manner dependent on IFN-I. Mouse results revealed that manidipine reduced CVB3 lethality, viral loads, and organ damage of infected mice with elevated levels of IFN-β protein and mRNAs encoding IFN-β and interferon-stimulated genes (ISGs), especially in the liver. Mechanism studies showed that manidipine enhanced the levels of mRNAs encoding IFN-β or ISG, IFNB1 promoter activity, and IFN-β induction pathways of both RLR and STING in infected HuH7 cells. Overall, CVB3 infection increases Ca2+ influx to suppress IFN-β, and blocking Ca2+ influx has the potential to reduce CVB3 infection by enhancing IFN-β.

Fruits are important dietary sources of nutrients, phytochemicals and antioxidants essential for human health. In many developing countries, calcium carbide (CaC2) is widely used as a low-cost artificial ripening agent despite its associated health risks. This study evaluated the impact of CaC2 ripening on the nutritional composition, phytochemical content, antioxidant properties and elemental profile of banana (Musa spp.), mango (Mangifera indica) and plantain (Musa paradisiaca). Fruits were naturally ripened (control) or treated with 10 or 30&#x2009;g/kg CaC2. Standard analytical methods were used to determine proximate composition, phytochemicals, antioxidant activity (DPPH, FRAP and TPC), vitamins, mineral elements and heavy metals. CaC2 treatment significantly increased ash content while reducing protein, carbohydrate and lipid levels, with fibre responses varying among fruits. Phytochemical profiles were altered in a dose-dependent and fruit-specific manner, including reductions in alkaloids and polyphenols and increases in flavonoids and tannins. Antioxidant vitamins (C and E) decreased significantly (p < 0.05), and antioxidant activities were generally suppressed, particularly DPPH radical scavenging capacity. Mineral concentrations increased due to contributions from CaC2, while toxic heavy metals (arsenic, lead and cadmium) were present in CaC2 and accumulated significantly in treated fruits, with arsenic showing the greatest increase. Collectively, these changes indicate that CaC2 not only accelerates ripening but may also promote progression toward overripening, leading to nutrient depletion and biochemical deterioration. This study provides an integrated, multiparameter evaluation of CaC2-induced ripening across multiple climacteric fruits and demonstrates direct transfer of toxic contaminants into edible tissues. The findings highlight significant food safety concerns and underscore the need for stricter regulation, control and the promotion of safer, sustainable ripening alternatives.

Papaya fruits have a high content of bioactive compounds that provide them high antioxidant capacity; however, these fruits undergo rapid deterioration processes once harvested, which implies a decrease in antioxidant activity. In order to reduce the oxidative stress that causes deterioration in the fruit, it is important to use technologies to increase the antioxidant system of the fruit. In that sense, the aim of this work was to evaluate the effect of a hydrothermal treatment (HT), calcium chloride (CaCl2), and their combination (HT-CaCl2) on the physicochemical quality and the enzymatic and nonenzymatic antioxidant systems of papaya fruits. Harvested papaya was treated with HT (48&#xb0;C, 25&#x2009;min), CaCl2 (1% w/v), and the combination HT-CaCl2 followed by storage at 12&#xb0;C for 20&#x2009;days. Physicochemical quality (weight loss, external color, and firmness), bioactive compounds (ascorbic acid [AA], total phenolics, and carotenoid content), antioxidant capacity (ABTS and DPPH), and the activity of antioxidant system enzymes (peroxidase [POD] and ascorbate peroxidase [APX]) were evaluated. In this regard, HT-CaCl2 was the most effective treatment in controlling weight loss, preserving the external fruit color, and maintaining the firmness. Furthermore, HT-CaCl2 boosted the fruit antioxidant properties by maintaining the amount of ascorbic acid and increasing total phenolics and carotenoids. Thus, fruits treated with HT-CaCl2 showed a higher antioxidant capacity as well as increased activity of the enzymes of the antioxidant system. In general, HT-CaCl2 can be used as an effective treatment to enhance antioxidant properties by maintaining bioactive compounds and increasing antioxidant enzymes, as well as maintaining the physicochemical quality of papaya fruits.

Synchronous calcium (Ca2+) bursting is a hallmark of neuronal network maturation. While microelectrode array (MEA) recordings are routinely used to generate population-averaged measurements on this functional network activity, live cell Ca2+-imaging offers single-cell resolved, contextual data. Unfortunately, most electrophysiologically active cells are hypersensitive to medium exchange, which is standard practice in most sensor dye-based Ca2+-imaging protocols. Here, we found that the use of conditioned imaging medium preserves spontaneous network activity of iPSC-derived glutamatergic and motor neuron cultures. The effect was consistent across different cell lines and seeding densities and allowed for the faithful detection of disease-specific phenotypes, as shown using a KCNQ2-related epilepsy model. Our findings thus provide a simple, robust strategy to measure spontaneous network activity in Ca2+-imaging experiments, broadening the utility of this technique for functional phenotyping, disease modeling, and drug screening with cellular resolution.

Patients with inflammatory bowel disease (IBD) have increased atherosclerotic cardiovascular risk that may be underestimated by conventional factors. Whether coronary artery calcium (CAC) progression adds prognostic value beyond baseline CAC in IBD is unclear. In this multicenter retrospective cohort, 467 IBD patients without known atherosclerotic cardiovascular disease underwent &#x2265;2 routine non-contrast chest CT scans (mean interval 21.2 months). CAC progression was defined as incident CAC (0 to >0), absolute progression (0&#x2009;<&#x2009;baseline <100 with annualized increase &#x2265;10), or relative progression (baseline &#x2265;100 with annualized increase &#x2265;10%). Major adverse cardiovascular events (MACE) were the primary outcome; incident atrial fibrillation (AF) was secondary. Cox proportional hazard regression was utilized to estimate hazard ratios (HRs) for time to MACE regarding CAC progression. Incremental value was assessed by C-index and continuous net reclassification improvement (NRI). Over a median follow-up of 37 months, 59 patients had MACE and 41 developed AF. CAC progression occurred in 27.6% and predicted MACE (HR 7.41, P&#x2009;<&#x2009;0.001), with graded risk (relative HR 10.31; absolute HR 8.14; incident HR 5.22; all P&#x2009;<&#x2009;0.001). Adding CAC progression to conventional factors improved discrimination (C-index 0.67 vs. 0.73) and reclassification (NRI 0.22, P&#x2009;<&#x2009;0.001), whereas baseline CAC added modest value (C-index 0.67 vs. 0.68; NRI 0.04, P&#x2009;=&#x2009;0.021). CAC progression was also associated with incident AF. Opportunistic CAC progression assessment from routine chest CT improves cardiovascular risk stratification in IBD beyond conventional factors and baseline CAC, including among patients with zero baseline CAC.

Empasiprubart (ARGX-117) is a humanized recycling antibody that prevents binding of C2 to C4b, blocking downstream classical and lectin pathways of complement activation. Empasiprubart binds to the CCP2 domain of complement component C2 in a calcium- and pH-dependent manner, leveraging physiological differences between blood and endosomal environments to facilitate the release and subsequent degradation of bound C2. The molecule incorporates Fc region mutations (H433K and N434F) that enhance its affinity for the neonatal Fc receptor (FcRn) under acidic endosomal conditions, thereby prolonging its in vivo half-life and supporting its recycling capacity. However, despite the earlier description of the complex structure, the molecular mechanism underlying these dependencies has remained elusive. Here, we further explored the crystal structure of the empasiprubart fragment antigen-binding (Fab) complexed to a C2 fragment, and provide a molecular rationale for its unique properties, while recognizing that not all contributing factors have been fully elucidated. Our observations indicate that the pH-dependent target release is rooted in a subtle intramolecular complementarity-determining region (CDR) destabilization, rather than direct modulation of the binding interface, and highlight the interplay between framework residues and CDRs. Collectively, our results not only lead to a better understanding of the mode of action of empasiprubart but also demonstrate the pivotal role of framework residues in the orchestration of antibody CDR function for non-trivial target binding.

Acute ischemic stroke remains a major cause of death and disability, underscoring the need for safe and effective neuroprotective strategies. Hydrogen sulfide (H&#x2082;S) exhibits dose-dependent neuroprotective effects but its therapeutic application is constrained by volatility and burst release. We synthesized low-solubility, slowly hydrolyzing calcium sulfide nanoparticles (CaS NPs) via a wet-chemistry route as an intrinsically slow-releasing H&#x2082;S donor. Their sustained release profile was characterized, and efficacy was evaluated in vitro using SH-SY5Y cells under oxygen-glucose deprivation/reoxygenation (OGD/R) and in BV2 microglia, and in vivo using a distal middle cerebral artery occlusion (dMCAO) mouse model. CaS NPs demonstrated sustained H&#x2082;S release over 48 h. In vitro, they enhanced SH-SY5Y cell viability under OGD/R, decreased intracellular reactive oxygen species, suppressed TNF-&#x3b1; and IL-1&#x3b2; expression in BV2 cells, and reduced neuronal apoptosis. In the dMCAO model, CaS NPs increased cortical H&#x2082;S levels, improved 24-h neurological scores, reduced day-3 infarct area, preserved peri-infarct neurons, mitigated ROS accumulation, and attenuated astrocyte and microglia activation. Treatment consistently decreased Bax expression, increased Bcl-2 levels, and reduced pro-inflammatory cytokine expression. Short-term safety assessments indicated a favorable biosafety profile. Collectively, these findings provide proof-of-concept support that CaS NPs can serve as a slow-releasing H&#x2082;S donor platform for further evaluation in experimental ischemic stroke."

This paper proposes the use of laser-assisted cutting technology to control the brittle-plastic transition of single-crystal CaF2 through local thermal softening, thereby suppressing its processing anisotropy. Nano-scratch experiments show that heating significantly increases the critical plastic cutting depth of each crystal plane and reduces the inter-plane differences. Based on this, laser-assisted ultra-precision turning was used to fabricate CaF2 optical microcavities with a surface roughness below 10 nm, achieving a maximum quality factor of ~7.79 &#xd7; 107, and significantly reducing the performance differences among different crystal orientations. The research indicates that this method can effectively promote uniform plastic flow on each crystal plane, providing an effective approach for the high-performance and consistent fabrication of anisotropic brittle optical components.

Activity-dependent modulation of presynaptic voltage-gated Ca 2+ channels (Ca V 2) regulates Ca 2+ influx to control neuronal circuit output. Although Ca V 2.1 can undergo robust Ca 2+ dependent facilitation (CDF), whether it occurs in native central nervous system neuronal circuits is disputed. Accurate auditory information processing requires precise and reliable synaptic transmission at high activity rates in the auditory brainstem. To determine if Ca V 2.1 CDF is a key regulator of high-fidelity synaptic transmission, we expressed Ca V 2.1 splice variants capable (Ca V 2.1 37a) or incapable (Ca V 2.1 37b) of CDF at the calyx of Held presynaptic terminal in the auditory brainstem. We found no difference in basal Ca V 2.1 currents or synaptic transmission. However, Ca V 2.1 37b terminals lacked CDF, synaptic facilitation and had a decreased reliability and precision of postsynaptic action-potential firing. Additionally, the Wave III amplitude of the auditory brainstem responses was reduced. We propose that Ca V 2.1 CDF is essential for accurate auditory information processing.