Search Results (182)

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction. Full article

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that maladaptive remodeling of these channels is the cause of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Recent experimental, translational, and clinical studies have improved our understanding of the roles LTCC expression, micro-domain trafficking, and post-translational control have in disrupting excitation–contraction coupling, provoking arrhythmias, and shaping phenotype specific hemodynamic compromise. We performed a systematic search of the PubMed and Google Scholar databases (2015–2025, English) and critically evaluated 17 eligible publications in an effort to organize the expanding body of work. This review combines existing data about LTCC density and T-tubule architecture with β-adrenergic and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and downstream sarcoplasmic reticulum crosstalk to explain how HFrEF presents with contractile insufficiency and how HFpEF shows diastolic calcium overload and stiffening. Additionally, we highlight the emerging therapeutic strategies aimed at restoring calcium homeostasis such as CaMKII inhibitors, ryanodine receptor type 2 (RyR2) stabilizers, and selective LTCC modulators without compromising systolic reserve. The review establishes LTCC dysregulation as a single mechanism that causes myocardial dysfunction while remaining specific to each phenotype, thus offering clinicians and researchers a complete reference for current concepts and future precision therapy approaches in heart failure. Full article

Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. However, the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of Cacna1c have increased basal corticosterone levels in the periphery and reduced the expression of Nr3c1 encoding the glucocorticoid receptor in the hippocampus and hypothalamus. These results are consistent, with an effect of Cacna1c dosage on hypothalamus–pituitary–adrenal (HPA) axis function. Heterozygous Cacna1c rats had lower levels of the histone markers H3K4me3 and H3K27acat exon 1₇ of the Nr3c1 gene. These histone modifications are typically linked to increased gene expression, but here were not associated with changes in the expression of exon 1₇ variants under non-stress conditions. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity with the altered activity of the HPA axis and function in the resting state, and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress. Full article

The intricate brain–heart interaction, essential for physiological balance, is largely governed by the autonomic nervous system (ANS). This bidirectional communication, involving both the sympathetic and parasympathetic branches of the ANS, is critical for maintaining cardiac homeostasis. Dysregulation of the ANS is a significant factor in cardiovascular diseases. Beyond the ANS, higher brain functions, particularly through interoceptive prediction, contribute to this dynamic interplay. The Cav1.3 L-type calcium channel, expressed in both the central nervous system (CNS) and the heart, is crucial for this interaction. Cav1.3, a key regulator of cellular excitability, exhibits genetic variations that are linked to both neurological and cardiac disorders, highlighting its pivotal role in the brain–heart axis. This review aims to delve into the under-explored role of Cav1.3 in brain–heart interaction, specifically examining how it modulates ANS activity and, consequently, the cardiac function. This will illuminate its significant role in the broader context of brain–heart interactions. Full article

Unconventional heavy oil reservoirs are particularly susceptible to steam breakthrough, which significantly reduces crude oil production. Profile control is a crucial strategy used for stabilizing oil production and minimizing production costs in these reservoirs. Conventional plugging agent systems used in the thermal recovery of heavy oil currently fail to meet the high-temperature, high-strength, and deep profile control requirements of this process. Precipitation-type calcium salt blocking agents demonstrate long-term stability at 300 °C and concentrations up to 250,000 mg/L, making them highly effective for profile control and channeling blockage during the steam injection stages of heavy oil recovery. This study proposes two types of precipitation-type calcium salt blocking agents: CaSO₄ and CaCO₃ crystals. The precipitation behavior of these agents was investigated, and their dynamic growth patterns were examined. The calcium sulfate blocking agent exhibits a slower crystal precipitation rate, allowing for a single-solution injection, while the calcium carbonate blocking agent precipitates rapidly, requiring a dual-solution injection. Both systems incorporate scale inhibitors to delay the growth of calcium salt crystals, which aids in deep profile control. Through microscopic visualization experiments, the micro-blocking characteristics of the calcium salt blocking agent systems within pores were compared, elucidating the blocking positions of the precipitated calcium salts under porous conditions. Calcium sulfate crystals preferentially precipitate in and block larger pore channels, whereas calcium carbonate crystals are more evenly distributed throughout the pore channels, reducing the reservoir’s heterogeneity. The final single-core displacement experiment demonstrated the sealing properties of the precipitation-type calcium salt blocking agent systems. The developed precipitation-type calcium salt blocking agent systems exhibit excellent profile control performance. Full article

Voltage-gated Ca²⁺ (Ca_V) channels are transmembrane proteins comprising the pore-forming subunit Ca_Vα₁ and the ancillary proteins Ca_Vα₂δ and Ca_Vβ. They are expressed in various tissues, including the nervous system, where they regulate Ca²⁺ entry in response to membrane potential changes. The increase in intracellular Ca²⁺ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the Ca_Vβ auxiliary subunit of the Ca_V2.1 (P/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other Ca_V channel subtypes, such as Ca_V1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson’s disease (PD). Here, we found potential phosphorylation sites for LRRK2 in Ca_Vβ₃ and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant Ca_V1.3 channels, both with and without wild-type LRRK2 or its LRRK2^G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2^G2019S significantly increases current density through Ca_V1.3 channels, and this effect depends on the presence of Ca_Vβ₃. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of Ca_Vβ₃ is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2^G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type Ca_V1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD. Full article

Background: Chronic Kidney Disease (CKD) affects 8–16% of the population worldwide and is characterized by an estimated Glomerular Filtration Rate (eGFR) of less than 60 mL/min/1.73 m² for more than 3 months. The main purpose of the study is to record the treatment algorithms and disease management of patients presenting for the first time to hospital-based nephrologists with a reduced eGFR and CKD diagnosis, under real-world clinical practice in Greece. Methods: This is the 6-month interim analysis of an ongoing, multicenter, observational, prospective, national study, which included 178 patients, with an eGFR between <60 and 15 mL/min/1.73 m², presenting for the first time to nephrologists at 15 public hospital units. Results: The median age of the patients was 71 years old, with 39.6% of them categorized as CKD stage G3b. Of these patients, 71.6% and 33.7% suffered from arterial hypertension and type 2 diabetes mellitus, respectively; 78.7% of patients received antihypertensive and 38.5% antidiabetic medications. Calcium channel blocker usage increased with disease progression (from 52.2% at G3a, to 67.9% and 67.6% at G3b and G4, respectively), while that of angiotensin II receptor antagonists decreased (from 78.3% at G3a, to 41.5% and 17.6% at G3b and G4, respectively). A decrease in metformin usage and an increase in Dipeptidyl peptidase-4 inhibitor (DPP4i) usage was also observed upon disease progression. Furthermore, 18.5%, 32.0% and 7.7% of patients received Sodium-glucose cotransporter-2 inhibitors (SGLT2i) at the G3a, G3b and G4 stages, respectively. Conclusions: The interim analysis results contributed to the collection of real-world data for the therapeutic patterns and the management of CKD in Greece. Full article

Background: Transforming growth factor-β (TGF-β) and interleukin 1β (IL-1β) are key regulators of the chondrogenic differentiation, physiology and pathology of cartilage tissue, with TGF-β promoting chondrogenesis and matrix formation, while IL-1β exerts catabolic effects, inhibiting chondrogenesis and contributing to cartilage degradation. Both cytokines alter the intracellular calcium ion (iCa²⁺) levels; however, the exact pathways are not known. Objectives: This study aimed to evaluate the impact of TGF-β3 and IL-1β on calcium homeostasis in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and chondrocytes during chondrogenesis. Results: TGF-β3 increased iCa²⁺ levels in both hBM-MSCs and chondrocytes. Furthermore, TGF-β3 increased the functional activity of L-type voltage-operated calcium channels (L-VOCCs) in hBM-MSCs but not in chondrocytes. TGF-β3 and IL-1β reduced L-VOCCs subunit CaV1.2 (CACNA1C) gene expression in chondrocytes. In hBM-MSCs, TGF-β3 and IL-1β increased SERCA pump (ATP2A2) gene expression, while in chondrocytes, this effect was observed only with TGF-β3. Conclusions: TGF-β3 increases iCa²⁺ both in osteoarthritic chondrocytes and hBM-MSCs during chondrogenesis. In hBM-MSCs, TGF-β3-mediated elevation in iCa²⁺ is related to the increased functional activity of L-VOCCs. IL-1β does not change iCa²⁺ in osteoarthritic chondrocytes and hBM-MSCs; however, it initiates the mechanisms leading to further downregulation of iCa²⁺ in both types of cells. The differential and cell-specific roles of TGF-β3 and IL-1β in the calcium homeostasis of osteoarthritic chondrocytes and hBM-MSCs during chondrogenesis may provide a new insight into future strategies for cartilage repair and osteoarthritis treatment. Full article

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, highliting the urgent need for new therapeutic strategies. Peptide-based therapies have demonstrated significant potential for treating CVDs; however, their clinical application is hindered by their limited stability in physiological fluids. To overcome this challenge, an effective drug delivery system is essential to protect and efficiently transport peptides to their intended targets. This study introduces two distinct strategies for loading a cardio-specific mimetic peptide (MP), previously designed to modulate L-type calcium channel function in cardiomyocytes, onto calcium phosphate nanoparticles (CaP NPs). MP-loaded CaP NPs were prepared by two different wet precipitation syntheses, one of which involved the use of sodium polyacrylate as a templating agent. Characterization of MP-loaded CaP NPs showed that their crystallinity, size, surface charge, and morphology could be tuned by adjusting the synthesis parameters. In vitro tests on cardiac cells confirmed that both types of MP-loaded CaP NPs are biocompatible with HL-1 cardiomyocytes and restored intracellular calcium flux under stressed conditions, highlighting their therapeutic potential. These results pave the way for further optimization of CaP NP formulations and suggest their potential as a viable nanomaterial for CVD treatment. Full article

CACNA1C encodes the α1c subunit of the L-type Ca²⁺ channel, Cav1.2. Ventricular myocytes from haploinsufficient Cacna1c (Cacna1c^+/−) rats exhibited reduced expression of Cav1.2 but an apparently normal sarcolemmal Ca²⁺ influx with an impaired response to sympathetic stress. We tested the hypothesis that the altered phosphorylation of Cav1.2 might underlie the sarcolemmal Ca²⁺ influx phenotype in Cacna1c^+/− myocytes using immunoblotting of the left ventricular (LV) tissue from Cacna1c^+/− versus wildtype (WT) hearts. Activation of cAMP-dependent protein kinase A (PKA) increases L-type Ca²⁺ current and phosphorylates Cav1.2 at serine-1928. Using an antibody directed against this phosphorylation site, we observed elevated phosphorylation of Cav1.2 at serine-1928 in LV myocardium from Cacna1c^+/− rats under basal conditions (+110% versus WT). Sympathetic stress was simulated by isoprenaline (100 nM) in Langendorff-perfused hearts. Isoprenaline increased the phosphorylation of serine-1928 in Cacna1c^+/− LV myocardium by ≈410%, but the increase was significantly smaller than in WT myocardium (≈650%). In conclusion, our study reveals altered PKA-dependent phosphorylation of Cav1.2 with elevated phosphorylation of serine-1928 under basal conditions and a diminished phosphorylation reserve during β-adrenergic stimulation. These alterations in the phosphorylation of Cav1.2 may explain the apparently normal sarcolemmal Ca²⁺ influx in Cacna1c^+/− myocytes under basal conditions as well as the impaired response to sympathetic stimulation. Full article

The healing process involves cell migration, which is sustained by an electrical potential difference that emerges between the edges of skin wounds and the center of the wound. The electrical potential in cells’ membranes is responsible for their migration in an electric field. The differences in the transmembrane electrochemical gradient generate this potential. The concomitant blockade of potassium and calcium channels by amiodarone at a medium dosage favored wound healing, but the effect was less intense than in the case of the selective blocking of potassium channels. According to this suggestion, blocking calcium channels might have a partial effect on blocking potassium channels. Given that nimodipine inhibits both L-type and T-type calcium channels, we aimed to investigate which of these calcium channels are involved in wound healing. Hence, we performed an experimental study in which nimodipine was used in three concentrations: 200 nM, which blocks only L-type calcium channels, 1000 nM, which blocks both L-type and T-type calcium channels, and 10,000 nM, which blocks calcium channels and activates CB1 cannabinoid receptors, respectively. The present research is a continuation of previous studies conducted by us, aimed to propose new perspectives on wound treatment. In conclusion, the blocking of calcium channels favored wound healing under our experimental conditions, but this happened only by simultaneously blocking the L-type and T-type calcium channels, because only the medium nimodipine concentration had a statistically significant effect. Full article

Peptide Lv is a small endogenous secretory peptide with ~40 amino acids and is highly conserved among certain several species. While it was first discovered that it augments L-type voltage-gated calcium channels (LTCCs) in neurons, thus it was named peptide “Lv”, it can bind to vascular endothelial growth factor receptor 2 (VEGFR2) and has VEGF-like activities, including eliciting vasodilation and promoting angiogenesis. Not only does peptide Lv augment LTCCs in neurons and cardiomyocytes, but it also promotes the expression of intermediate-conductance K_Ca channels (K_Ca3.1) in vascular endothelial cells. Peptide Lv is upregulated in the retinas of patients with early proliferative diabetic retinopathy, a disease involving pathological angiogenesis. This review will provide an overview of peptide Lv, its known bioactivities in vitro and in vivo, and its clinical relevance, with a focus on its role in angiogenesis. As there is more about peptide Lv to be explored, this article serves as a foundation for possible future developments of peptide Lv-related therapeutics to treat or prevent diseases. Full article

Calcium ions (Ca²⁺) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of excitotoxicity, the excessive release of glutamate in the synapses can trigger the activation of postsynaptic receptors. Upon activation, Ca²⁺ influx into the cell from the extracellular space via their associated ion channels, most notably L-type Ca²⁺ channels. Previous studies have indicated that α-synuclein (α-syn), a typical cytosolic protein, plays a significant role in the pathogenesis of Parkinson’s disease (PD). It is also worth noting that the aggregated form of α-syn has the capacity to affect Ca²⁺ homeostasis by altering the function of Ca²⁺ regulation. The upregulation of leucine-rich repeat kinase 2 (LRRK2) is closely associated with PD pathogenesis. LRRK2 mutants exhibit a dysregulation of calcium signaling, resulting in dopaminergic neuronal degeneration. It could therefore be proposed that α-syn and LRRK2 play important roles in the mechanisms underlying Ca²⁺ dyshomeostasis and excitotoxicity in PD. Full article

Background: α₂δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α₂δ-1) and CACNA2D3 (coding for α₂δ-3) genes were identified in patients with autism spectrum disorder (ASD). However, the pathogenicity of these variants is not known, and the molecular mechanism by which α₂δ proteins may contribute to the pathophysiology of autism is, as of today, not understood. Therefore, in this study we functionally characterized two heterozygous missense variants in α₂δ-1 (p.R351T) and α₂δ-3 (p.A275T), previously identified in patients with ASD. Methods: Electrophysiological recordings in transfected tsA201 cells were used to study specific channel-dependent functions of mutated α₂δ proteins. Membrane expression, presynaptic targeting, and trans-synaptic signaling of mutated α₂δ proteins were studied upon expression in murine cultured hippocampal neurons. Results: Homologous expression of both mutated α₂δ proteins revealed a strongly reduced membrane expression and synaptic localization compared to the corresponding wild type α₂δ proteins. Moreover, the A275T mutation in α₂δ-3 resulted in an altered glycosylation pattern upon heterologous expression. However, neither of the mutations compromised the biophysical properties of postsynaptic L-type (Ca_V1.2 and Ca_V1.3) and presynaptic P/Q-type (Ca_V2.1) channels when co-expressed in tsA201 cells. Furthermore, presynaptic expression of p.R351T in the α₂δ-1 splice variant lacking exon 23 did not affect trans-synaptic signaling to postsynaptic GABA_A receptors. Conclusions: Our data provide evidence that the pathophysiological mechanisms of ASD-causing mutations of α₂δ proteins may not involve their classical channel-dependent and trans-synaptic functions. Alternatively, these mutations may induce subtle changes in synapse formation or neuronal network function, highlighting the need for future α₂δ protein-linked disease models. Full article