Search Results (33)

Microglia, the unique and motile immune cells of the central nervous system (CNS), function as a security guard in maintaining CNS homeostasis, primarily through calcium signaling. The calcium dynamics in microglia control important functions such as phagocytosis, cytokine release, and migration. Calcium dysregulation in microglia has been linked to several CNS disorders, like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke (IS). Calcium entering through channels such as voltage-gated calcium channels (VGCCs), store-operated calcium entry (SOCE), and transient receptor potential (TRP) channels is essential for microglial activation and pro-inflammatory responses. Under pathological conditions, like the formation of amyloid-β plaques in AD, aggregation of α-synuclein in PD, and oxidative stress in MS, calcium dysregulation exacerbates neuroinflammation, mitochondrial dysfunction, and neurodegeneration. Therapeutic strategies targeting calcium signaling pathways, using calcium channel blockers and antioxidant interventions, show promise for alleviating microglial activation and slowing down disease progression. This review summarizes the underlying mechanisms of microglial calcium dysregulation and potential therapeutic benefits for restoring microglial calcium balance in CNS disorders. Full article

The roles of perinatal development, intracellular calcium [Ca²⁺]i, and synaptogenesis disruption are not novel in the autism/ASD literature. The focus on six mechanisms controlling synaptogenesis, each regulated by [Ca²⁺]i, and each aberrant in ASDs is novel. The model presented here predicts that autism epidemic causation involves central roles of both electromagnetic fields (EMFs) and chemicals. EMFs act via voltage-gated calcium channel (VGCC) activation and [Ca²⁺]i elevation. A total of 15 autism-implicated chemical classes each act to produce [Ca²⁺]i elevation, 12 acting via NMDA receptor activation, and three acting via other mechanisms. The chronic nature of ASDs is explained via NO/ONOO(-) vicious cycle elevation and MeCP2 epigenetic dysfunction. Genetic causation often also involves [Ca²⁺]i elevation or other impacts on synaptogenesis. The literature examining each of these steps is systematically examined and found to be consistent with predictions. Approaches that may be sed for ASD prevention or treatment are discussed in connection with this special issue: The current situation and prospects for children with ASDs. Such approaches include EMF, chemical avoidance, and using nutrients and other agents to raise the levels of Nrf2. An enriched environment, vitamin D, magnesium, and omega-3s in fish oil may also be helpful. Full article

Far-infrared (FIR), characterized by its specific electromagnetic wavelengths, has emerged as an adjunctive therapeutic strategy for various diseases, particularly in ameliorating manifestations associated with renal disorders. Although FIR was confirmed to possess antioxidative and anti-inflammatory attributes, the intricate cellular mechanisms through which FIR mitigates lead (Pb)-induced nephrotoxicity remain enigmatic. In this study, we investigated the effects of FIR on Pb-induced renal damage using in vitro and in vivo approaches. NRK52E rat renal cells exposed to Pb were subsequently treated with ceramic-generated FIR within the 9~14 μm range. Inductively coupled plasma mass spectrometry (ICP-MS) enabled quantitative Pb concentration assessment, while proteomic profiling unraveled intricate cellular responses. In vivo investigations used Wistar rats chronically exposed to lead acetate (PbAc) at 6 g/L in their drinking water for 15 weeks, with or without a concurrent FIR intervention. Our findings showed that FIR upregulated the voltage-gated calcium channel, voltage-dependent L type, alpha 1D subunit (CaV1.3), and myristoylated alanine-rich C kinase substrate (MARCKS) (p < 0.05), resulting in increased calcium influx (p < 0.01), the promotion of mitochondrial activity, and heightened ATP production. Furthermore, the FIR intervention effectively suppressed ROS production, concurrently mitigating Pb-induced cellular death. Notably, rats subjected to FIR exhibited significantly reduced blood Pb levels (30 vs. 71 μg/mL; p < 0.01), attenuated Pb-induced glomerulosclerosis, and enhanced Pb excretion compared to the controls. Our findings suggest that FIR has the capacity to counteract Pb-induced nephrotoxicity by modulating calcium influx and optimizing mitochondrial function. Overall, our data support FIR as a novel therapeutic avenue for Pb toxicity in the kidneys. Full article

The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN. Full article

Voltage-gated calcium channels (VGCCs) are targeted to treat pain conditions. Since the discovery of their relation to pain processing control, they are investigated to find new strategies for better pain control. This review provides an overview of naturally based and synthetic VGCC blockers, highlighting new evidence on the development of drugs focusing on the VGCC subtypes as well as mixed targets with pre-clinical and clinical analgesic effects. Full article

Critical bone defects are the most difficult challenges in the area of tissue repair. Polycaprolactone (PCL) scaffolds, associated with hydroxyapatite (HA) and tricalcium phosphate (TCP), are reported to have an enhanced bioactivity. Moreover, the use of electrical stimulation (ES) has overcome the lack of bioelectricity at the bone defect site and compensated the endogenous electrical signals. Such treatments could modulate cells and tissue signaling pathways. However, there is no study investigating the effects of ES and bioceramic composite scaffolds on bone tissue formation, particularly in the view of cell signaling pathway. This study aims to investigate the application of HA/TCP composite scaffolds and ES and their effects on the Wingless-related integration site (Wnt) pathway in critical bone repair. Critical bone defects (25 mm²) were performed in rats, which were divided into four groups: PCL, PCL + ES, HA/TCP and HA/TCP + ES. The scaffolds were grafted at the defect site and applied with the ES application twice a week using 10 µA of current for 5 min. Bone samples were collected for histomorphometry, immunohistochemistry and molecular analysis. At the Wnt canonical pathway, HA/TCP and HA/TCP + ES groups showed higher Wnt1 and β-catenin gene expression levels, especially HA/TCP. Moreover, HA/TCP + ES presented higher Runx2, Osterix and Bmp-2 levels. At the Wnt non-canonical pathway, HA/TCP group showed higher voltage-gated calcium channel (Vgcc), calmodulin-dependent protein kinase II, and Wnt5a genes expression, while HA/TCP + ES presented higher protein expression of VGCC and calmodulin (CaM) at the same period. The decrease in sclerostin and osteopontin genes expressions and the lower bone sialoprotein II in the HA/TCP + ES group may be related to the early bone remodeling. This study shows that the use of ES modulated the Wnt pathways and accelerated the osteogenesis with improved tissue maturation. Full article

Voltage-gated calcium channels (VGCCs) and estrogen receptors are important cellular proteins that have been shown to interact with each other across varied cells and tissues. Estrogen hormone, the ligand for estrogen receptors, can also exert its effects independent of estrogen receptors that collectively constitute non-genomic mechanisms. Here, we provide insights into the VGCC regulation by estrogen and the possible mechanisms involved therein across several cell types. Notably, most of the interaction is described in neuronal and cardiovascular tissues given the importance of VGCCs in these electrically excitable tissues. We describe the modulation of various VGCCs by estrogen known so far in physiological conditions and pathological conditions. We observed that in most in vitro studies higher concentrations of estrogen were used while a handful of in vivo studies used meager concentrations resulting in inhibition or upregulation of VGCCs, respectively. There is a need for more relevant physiological assays to study the regulation of VGCCs by estrogen. Additionally, other interacting receptors and partners need to be identified that may be involved in exerting estrogen receptor-independent effects of estrogen. Full article

Unidentified pathogenetic mechanisms and genetic and clinical heterogeneity represent critical factors hindering the development of treatments for inherited retinal dystrophies. Frameshift mutations in Cacna2d4, which codes for an accessory subunit of voltage-gated calcium channels (VGCC), cause cone-rod dystrophy RCD4 in patients, but the underlying mechanisms remain unknown. To define its pathogenetic mechanisms, we investigated the impact of a Cacna2d4 frameshift mutation on the electrophysiological profile and calcium handling of mouse rod photoreceptors by patch-clamp recordings and calcium imaging, respectively. In mutant (MUT) rods, the dysregulation of calcium handling extends beyond the reduction in calcium entry through VGCC and surprisingly involves internal calcium stores’ depletion and upregulation of calcium entry via non-selective cationic channels (CSC). The similar dependence of CSC on basal calcium levels in WT and MUT rods suggests that the primary defect in MUT rods lies in defective calcium stores. Calcium stores’ depletion, leading to upregulated calcium and sodium influx via CSC, represents a novel and, so far, unsuspected consequence of the Cacna2d4 mutation. Blocking CSC may provide a novel strategy to counteract the well-known pathogenetic mechanisms involved in rod demise, such as the reticulum stress response and calcium and sodium overload due to store depletion. Full article

The α₂δ subunit is a high-voltage activated (HVA) calcium channel (Ca_v1 and Ca_v2) auxiliary subunit that increases the density and function of HVA calcium channels in the plasma membrane of mammals. However, its function in plant parasitic nematodes remains unknown. In this study, we cloned the full-length cDNA sequence of the voltage-gated calcium channel (VGCC) α₂δ subunit (named DdCa_vα₂δ) in Ditylenchus destructor. We found that DdCa_vα₂δ tends to be expressed in the egg stage, followed by the J3 stage. RNA-DIG in situ hybridization experiments showed that the DdCa_vα₂δ subunit was expressed in the body wall, esophageal gland, uterus, post uterine, and spicules of D. destructor. The in vitro application of RNA interference (RNAi) affected the motility, reproduction, chemotaxis, stylet thrusting, and protein secretion of D. destructor to different degrees by targeting DdCα1D, DdCα1A, and DdCa_vα₂δ in J3 stages, respectively. Based on the results of RNAi experiments, it was hypothesized that L-type VGCC may affect the motility, chemotaxis, and stylet thrusting of D. destructor. Non-L-type VGCC may affect the protein secretion and reproduction of D. destructor. The DdCa_vα₂δ subunit gene also affected the motility, chemotaxis, and reproduction of D. destructor. These findings reveal the independent function of the VGCC α₂δ subunit in D. destructor as well as give a theoretical foundation for future research on plant parasitic nematode VGCC. Full article

Tetrabromobisphenol A (TBBPA) is a flame retardant widely used to reduce flammability. It is an endocrine disruptor, and due to constant human exposure, some concerns have been raised regarding its impact on human health. Studies showed that TBBPA affects oxidative stress, cell proliferation and intracellular calcium levels. However, the vascular consequences of TBBPA exposure are still relatively unexplored. Hence, this work aimed to analyse TBBPA effects on rat aortic smooth muscle and its action mechanisms. Through an ex vivo approach, Wistar rat aortas were used in an organ bath to evaluate the vascular effect of TBBPA (0.01–100 μM). Additionally, TBBPA’s mode of action was studied through calcium and potassium channel inhibitors. Resorting to in vitro studies, A7r5 cells were used to analyse L-Type voltage-gated calcium channel (VGCC) activity through the whole-cell configuration of the patch clamp technique, and the mRNA expression of proteins and ion channels involved in vascular contractility. The results showed vasorelaxation of rat aorta induced by TBBPA exposure, involving the inactivation of L-Type VGCC and activation of potassium channels, and the modulation of mRNA expression of L-type calcium and large-conductance calcium 1.1 and the BK_Ca 1.1 α- and β₁ -subunit channels, soluble guanylyl cyclase and protein Kinase G. Full article

N-methyl-D-aspartate (NMDA) receptors play a critical role in activity-dependent dendritic arborization, spinogenesis, and synapse formation by stimulating calcium-dependent signaling pathways. Previously, we have shown that brevetoxin 2 (PbTx-2), a voltage-gated sodium channel (VGSC) activator, produces a concentration-dependent increase in intracellular sodium [Na⁺]_I and increases NMDA receptor (NMDAR) open probabilities and NMDA-induced calcium (Ca²⁺) influxes. The objective of this study is to elucidate the downstream signaling mechanisms by which the sodium channel activator PbTx-2 influences neuronal morphology in murine cerebrocortical neurons. PbTx-2 and NMDA triggered distinct Ca²⁺-influx pathways, both of which involved the NMDA receptor 2B (GluN2B). PbTx-2-induced neurite outgrowth in day in vitro 1 (DIV-1) neurons required the small Rho GTPase Rac1 and was inhibited by both a PAK1 inhibitor and a PAK1 siRNA. PbTx-2 exposure increased the phosphorylation of PAK1 at Thr-212. At DIV-5, PbTx-2 induced increases in dendritic protrusion density, p-cofilin levels, and F-actin throughout the dendritic arbor and soma. Moreover, PbTx-2 increased miniature excitatory post-synaptic currents (mEPSCs). These data suggest that the stimulation of neurite outgrowth, spinogenesis, and synapse formation produced by PbTx-2 are mediated by GluN2B and PAK1 signaling. Full article

The α₂δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α₂δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α₂δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α₂δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α₂δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α₂δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α₂δ-1-3 isoforms (α₂δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α₂δ proteins. In contrast to this redundant presynaptic function, α₂δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α₁-α₂δ protein–protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α₂δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α₂δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α₂δ and Cachd1. Full article

Several mutations on neuronal voltage-gated Ca²⁺ channels (VGCC) have been shown to cause neurological disorders and contribute to the initiation of epileptic seizures, migraines, or cerebellar degeneration. Analysis of the functional consequences of these mutations mainly uses heterologously expressed mutated channels or transgenic mice which mimic these pathologies, since direct electrophysiological approaches on brain samples are not easily feasible. We demonstrate that mammalian voltage-gated Ca²⁺ channels from membrane preparation can be microtransplanted into Xenopus oocytes and can conserve their activity. This method, originally described to study the alteration of GABA receptors in human brain samples, allows the recording of the activity of membrane receptors and channels with their native post-translational processing, membrane environment, and regulatory subunits. The use of hippocampal, cerebellar, or cardiac membrane preparation displayed different efficacy for transplanted Ca²⁺ channel activity. This technique, now extended to the recording of Ca²⁺ channel activity, may therefore be useful in order to analyze the calcium signature of membrane preparations from unfixed human brain samples or normal and transgenic mice. Full article

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant. Full article

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson’s disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics. Full article