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The importance of the intracellular Ca concentration ([Ca ] ) in neutrophil function has been intensely studied. However, the role of the intracellular Na concentration ([Na ] ) which is closely linked to the intracellular Ca regulation has been largely overlooked. The [Na ] is regulated by Na transport proteins such as the Na /Ca -exchanger (NCX1), Na /K -ATPase, and Na -permeable, transient receptor potential melastatin 2 (TRPM2) channel. Stimulating with either N-formylmethionine-leucyl-phenylalanine (fMLF) or complement protein C5a causes distinct changes of the [Na ] . fMLF induces a sustained increase of [Na ] , surprisingly, reaching higher values in TRPM2 neutrophils. This outcome is unexpected and remains unexplained. In both genotypes, C5a elicits only a transient rise of the [Na ] . The difference in [Na ] measured at = 10 min after stimulation is inversely related to neutrophil chemotaxis. Neutrophil chemotaxis is more efficient in C5a than in an fMLF gradient. Moreover, lowering the extracellular Na concentration from 140 to 72 mM improves chemotaxis of WT but not of TRPM2 neutrophils. Increasing the [Na ] by inhibiting the Na /K -ATPase results in disrupted chemotaxis. This is most likely due to the impact of the altered Na homeostasis and presumably NCX1 function whose expression was shown by means of qPCR and which critically relies on proper extra- to intracellular Na concentration gradients. Increasing the [Na ] by a few mmol/l may suffice to switch its transport mode from forward (Ca -efflux) to reverse (Ca -influx) mode. The role of NCX1 in neutrophil chemotaxis is corroborated by its blocker, which also causes a complete inhibition of chemotaxis.

Homeostasis of inorganic phosphate (P i ) is primarily an affair of the kidneys. Reabsorption of the bulk of filtered P i occurs along the renal proximal tubule and is initiated by apically localized Na + -dependent P i cotransporters. Tubular P i reabsorption and therefore renal excretion of P i is controlled by a number of hormones, including phosphatonins, and metabolic factors. In most cases, regulation of P i reabsorption is achieved by changing the apical abundance of Na + /Pi cotransporters. The regulatory mechanisms involve various signaling pathways and a number of proteins that interact with Na + /P i cotransporters.

Diabetes mellitus is associated with natriuresis, whereas estrogen has been shown to be renoprotective in diabetic nephropathy and may independently regulate renal sodium reabsorption. The aim of this study was to determine the effects of 17-β estradiol (E2) replacement to diabetic, ovariectomized (OVX) female rats on the expression of major renal sodium transporters. Female, Sprague–Dawley rats (210 g) were randomized into four groups: (1) OVX; (2) OVX+E2; (3) diabetic+ovariectomized (D+OVX); and (4) diabetic+ovariectomized+estrogen (D+OVX+E2). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg·body weight (bw)). Rats received phytoestrogen-free diet and water ad libitum for 12 weeks. E2 attenuated hyperglycemia, hyperalbuminuria, and hyperaldosteronism in D rats, as well as the diabetes-induced changes in renal protein abundances for the bumetanide-sensitive Na–K–2Cl cotransporter (NKCC2), and the α- and β-subunits of the epithelial sodium channel (ENaC), that is, E2 decreased NKCC2, but increased α- and β-ENaC abundances. In nondiabetic rats, E2 decreased plasma K+ and increased urine K+/Na+ ratio, as well as decreased the abundance of NKCC2, β-ENaC, and α-1-Na–K–adenosine triphosphate (ATP)ase in the outer medulla. Finally, the diabetic, E2 rats had measurably lower final circulating levels of E2 than the nondiabetic E2 rats, despite an identical replacement protocol, suggesting a shorter biological half-life of E2 with diabetes. Therefore, E2 attenuated diabetes and preserved renal sodium handling and related transporter expression levels. In addition, E2 had diabetes-independent effects on renal electrolyte handling and associated proteins.

This study shows that a polymodal nociceptive sensory neuron in C. elegans detects both harsh body touch and noxious cold. Using calcium imaging and genetic tools, the researchers report that the same sensory neuron uses Degerin/Epithelial Na + channel proteins MEC-10 and DEGT-1 for harsh touch detection and TRPA-1 channel for cold sensing. Polymodal nociceptors detect noxious stimuli, including harsh touch, toxic chemicals and extremes of heat and cold. The molecular mechanisms by which nociceptors are able to sense multiple qualitatively distinct stimuli are not well understood. We found that the C. elegans PVD neurons are mulitidendritic nociceptors that respond to harsh touch and cold temperatures. The harsh touch modality specifically required the DEG/ENaC proteins MEC-10 and DEGT-1, which represent putative components of a harsh touch mechanotransduction complex. In contrast, responses to cold required the TRPA-1 channel and were MEC-10 and DEGT-1 independent. Heterologous expression of C. elegans TRPA-1 conferred cold responsiveness to other C. elegans neurons and to mammalian cells, indicating that TRPA-1 is a cold sensor. Our results suggest that C. elegans nociceptors respond to thermal and mechanical stimuli using distinct sets of molecules and identify DEG/ENaC channels as potential receptors for mechanical pain.

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.

Voltage-gated sodium channels play a critical role in cellular excitability, amplifying small membrane depolarizations into action potentials. Interactions with auxiliary subunits and other factors modify the intrinsic kinetic mechanism to result in new molecular and cellular functionality. We show here that sodium channels can implement a molecular leaky integrator, where the input signal is the membrane potential and the output is the occupancy of a long-term inactivated state. Through this mechanism, sodium channels effectively measure the frequency of action potentials and convert it into Na+ current availability. In turn, the Na+ current can control neuronal firing frequency in a negative feedback loop. Consequently, neurons become less sensitive to changes in excitatory input and maintain a lower firing rate. We present these ideas in the context of rat serotonergic raphe neurons, which fire spontaneously at low frequency and provide critical neuromodulation to many autonomous and cognitive brain functions.

In brain grey matter, excitatory synaptic transmission activates glutamate uptake into astrocytes, inducing sodium signals which propagate into neighboring astrocytes through gap junctions. These sodium signals have been suggested to serve an important role in neuro-metabolic coupling. So far, it is unknown if astrocytes in white matter—that is in brain regions devoid of synapses—are also able to undergo such intra- and intercellular sodium signalling. In the present study, we have addressed this question by performing quantitative sodium imaging in acute tissue slices of mouse corpus callosum. Focal application of glutamate induced sodium transients in SR101-positive astrocytes. These were largely unaltered in the presence of ionotropic glutamate receptors blockers, but strongly dampened upon pharmacological inhibition of glutamate uptake. Sodium signals induced in individual astrocytes readily spread into neighboring SR101-positive cells with peak amplitudes decaying monoexponentially with distance from the stimulated cell. In addition, spread of sodium was largely unaltered during pharmacological inhibition of purinergic and glutamate receptors, indicating gap junction-mediated, passive diffusion of sodium between astrocytes. Using cell-type-specific, transgenic reporter mice, we found that sodium signals also propagated, albeit less effectively, from astrocytes to neighboring oligodendrocytes and NG2 cells. Again, panglial spread was unaltered with purinergic and glutamate receptors blocked. Taken together, our results demonstrate that activation of sodium-dependent glutamate transporters induces sodium signals in white matter astrocytes, which spread within the astrocyte syncytium. In addition, we found a panglial passage of sodium signals from astrocytes to NG2 cells and oligodendrocytes, indicating functional coupling between these macroglial cells in white matter.

Several species of the genus Veratrum that produce steroid alkaloids are commonly used to treat pain and hypertension in China and Europe. However, Veratrum alkaloids (VAs) induce serious cardiovascular toxicity. In China, Veratrum treatment often leads to many side effects and even causes the death of patients, but the pathophysiological mechanisms under these adverse effects are not clear. Here, two solanidine-type VAs (isorubijervine and rubijervine) isolated from Veratrum taliense exhibited strong cardiovascular toxicity. A pathophysiological study indicated that these VAs blocked sodium channels NaV1.3–1.5 and exhibited the strongest ability to inhibit NaV1.5, which is specifically expressed in cardiac tissue and plays an essential role in cardiac physiological function. This result reveals that VAs exert their cardiovascular toxicity via the NaV1.5 channel. The effects of VAs on NaV1.3 and NaV1.4 may be related to their analgesic effect and skeletal muscle toxicity, respectively.

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na ) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na 1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na -specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na channel-mediated itch signalling. Na 1.7 showed substantial scratch reduction mainly towards strong pruritogens. Na 1.8 impaired histamine and 5-HT-induced scratching while Na 1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na 1.7 and indicated an overall contribution of Na 1.9. Beside the proposed general role of Na 1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na 1.8 to sustain prolonged itching. Therefore, Na 1.7 and 1.9 may represent targets in pruritus therapy.

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility. The SCN5A gene encodes Na v 1.5, the predominant cardiac sodium channel alpha subunit. SCN5A mutations have been identified in patients with arrhythmic disorders associated with DCM. The characterization of Na v 1.5 mutations located in the voltage sensor domain (VSD) and associated with DCM revealed divergent biophysical defects that do not fully explain the pathologies observed in these patients. The purpose of this study was to characterize the pathological consequences of a gating pore in the heart arising from the Na v 1.5/R219H mutation in a patient with complex cardiac arrhythmias and DCM. We report its properties using cardiomyocytes derived from patient-specific human induced pluripotent stem cells. We showed that this mutation generates a proton leak (called gating pore current). We also described disrupted ionic homeostasis, altered cellular morphology, electrical properties, and contractile function, most probably linked to the proton leak. We thus propose a novel link between SCN5A mutation and the complex pathogenesis of cardiac arrhythmias and DCM. Furthermore, we suggest that leaky channels would constitute a common pathological mechanism underlying several neuronal, neuromuscular, and cardiac pathologies.