Macrophage to neuron communication via extracellular vesicles in neuropathic pain conditions.

Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons.

Peripheral gating of mechanosensation by glial diazepam binding inhibitor.

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities.

Super-Resolution Analysis of the Origins of the Elementary Events of ER Calcium Release in Dorsal Root Ganglion Neurons.

Coordinated events of calcium (Ca) released from the endoplasmic reticulum (ER) are key second messengers in excitable cells. In pain-sensing dorsal root ganglion (DRG) neurons, these events can be observed as Ca sparks, produced by a combination of ryanodine receptors (RyR) and inositol 1,4,5-triphosphate receptors (IP3R1). These microscopic signals offer the neuronal cells with a possible means of modulating the subplasmalemmal Ca handling, initiating vesicular exocytosis.

Peripheral gating of pain by glial endozepine.

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating satellite glia-sensory neuron crosstalk in the dorsal root ganglion (DRG). DBI is highly and specifically expressed in satellite glia cells (SGCs) of mice, rat and human, but not in sensory neurons or other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without significant effects on other sensory modalities.

Redox regulation of K7 channels through EF3 hand of calmodulin.

Neuronal K7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site-mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B, constituting the calcium responsive domain (CRD).

Dorsal root ganglia control nociceptive input to the central nervous system.

Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here, in experiments on rats and mice, we show that the peripheral afferent nociceptive information undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics, we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG.

Intracellular zinc protects Kv7 K channels from Ca/calmodulin-mediated inhibition.

Zinc (Zn) is an essential trace element; it serves as a cofactor for a great number of enzymes, transcription factors, receptors, and other proteins. Zinc is also an important signaling molecule, which can be released from intracellular stores into the cytosol or extracellular space, for example, during synaptic transmission. Amongst cellular effects of zinc is activation of Kv7 (KCNQ, M-type) voltage-gated potassium channels.

Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through K7.4 channel upsurge in auditory neurons and hair cells.

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons [SGNs]).

Protein disulfide isomerase modulation of TRPV1 controls heat hyperalgesia in chronic pain.

Protein disulfide isomerase (PDI) plays a key role in maintaining cellular homeostasis by mediating protein folding via catalyzing disulfide bond formation, breakage, and rearrangement in the endoplasmic reticulum. Increasing evidence suggests that PDI can be a potential treatment target for several diseases. However, the function of PDI in the peripheral sensory nervous system is unclear.

Inferiority complex: why do sensory ion channels multimerize?

Peripheral somatosensory nerves are equipped with versatile molecular sensors which respond to acute changes in the physical environment. Most of these sensors are ion channels that, when activated, depolarize the sensory nerve terminal causing it to generate action potentials, which is the first step in generation of most somatic sensations, including pain. The activation and inactivation of sensory ion channels is tightly regulated and modulated by a variety of mechanisms.

Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.

Inflammation has recently emerged as an important contributor for cardiovascular disease development and participates pivotally in the development of neointimal hyperplasia and abdominal aortic aneurysms (AAA) formation. Kv7.4/KCNQ4, a K channel, is one of the important regulators of vascular function but its role in vascular inflammation is unexplored.

Activation of parabrachial nucleus - ventral tegmental area pathway underlies the comorbid depression in chronic neuropathic pain in mice.

Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically investigate the cellular mechanisms and circuits underlying the chronic-pain-induced depression behavior. We show that the development of chronic pain is accompanied by depressive-like behaviors in a mouse model of trigeminal neuralgia.

Neuropathic Injury-Induced Plasticity of GABAergic System in Peripheral Sensory Ganglia.

GABA is a major inhibitory neurotransmitter in the mammalian central nervous system (CNS). Inhibitory GABA channel circuits in the dorsal spinal cord are the gatekeepers of the nociceptive input from the periphery to the CNS. Weakening of these spinal inhibitory mechanisms is a hallmark of chronic pain.

Kv7 Channels and Excitability Disorders.

Kv7.1-Kv7.5 (KCNQ1-5) K channels are voltage-gated K channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K currents, such as neuronal M current and cardiac I.

Junctophilin-4 facilitates inflammatory signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons.

Key Points: Rat somatosensory neurons express a junctional protein, junctophilin-4 (JPH4) JPH4 is necessary for the formation of store operated Ca entry (SOCE) complex at the junctions between plasma membrane and endoplasmic reticulum in these neurons. Knockdown of JPH4 impairs endoplasmic reticulum Ca store refill and junctional Ca signalling in sensory neurons. In vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly attenuated experimentally induced inflammatory pain in rats.

A correlative super-resolution protocol to visualise structural underpinnings of fast second-messenger signalling in primary cell types.

Nanometre-scale cellular information obtained through super-resolution microscopies are often unaccompanied by functional information, particularly transient and diffusible signals through which life is orchestrated in the nano-micrometre spatial scale. We describe a correlative imaging protocol which allows the ubiquitous intracellular second messenger, calcium (Ca), to be directly visualised against nanoscale patterns of the ryanodine receptor (RyR) Ca channels which give rise to these Ca signals in wildtype primary cells. This was achieved by combining total internal reflection fluorescence (TIRF) imaging of the elementary Ca signals, with the subsequent DNA-PAINT imaging of the RyRs.

Vascular Kv7 channels control intracellular Ca dynamics in smooth muscle.

Voltage-gated Kv7 (or KCNQ) channels control activity of excitable cells, including vascular smooth muscle cells (VSMCs), by setting their resting membrane potential and controlling other excitability parameters. Excitation-contraction coupling in muscle cells is mediated by Ca but until now, the exact role of Kv7 channels in cytosolic Ca dynamics in VSMCs has not been fully elucidated. We utilised microfluorimetry to investigate the impact of Kv7 channel activity on intracellular Ca levels and electrical activity of rat A7r5 VSMCs and primary human internal mammary artery (IMA) SMCs.

Local Ca signals couple activation of TRPV1 and ANO1 sensory ion channels.

ANO1 (TMEM16A) is a Ca-activated Cl channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons.

Delineating an extracellular redox-sensitive module in T-type Ca channels.

T-type (Cav3) Ca channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.

Kv7.4 Channel Contribute to Projection-Specific Auto-Inhibition of Dopamine Neurons in the Ventral Tegmental Area.

Dopaminergic neurons in the ventral tegmental area (VTA) encode behavioral patterns important in reward and drug addiction as well as in emotional disorders. These functions of dopamine neurons are directly related to the release of dopamine in the targeted regions of the brain which are, thus, controlled by the excitability of dopamine neurons. One mechanism for modulation of dopamine neuronal excitability is mediated by the auto dopamine type 2 (D2) receptors, through activation of a Kir3/GIRK K channel which inhibits the firing of dopamine neurons.

Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex.

Kv4 pore-forming subunits co-assemble with β-subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K current (I). Compound NS5806 has been shown to potentate I in canine cardiomyocytes; however, its effects on I in other species yet to be determined. We found that NS5806 inhibited native I in a concentration-dependent manner (0.

Predictors and Clinical Outcomes in Empyema Thoracis Patients Presenting to the Emergency Department Undergoing Video-Assisted Thoracoscopic Surgery.

Background: Video-assisted thoracoscopic surgery (VATS) is widely used for the treatment of empyema. We evaluated clinical symptoms, laboratory examinations, and thoracentesis to assess patients in the emergency department (ED) with empyema thoracis, undergoing VATS to identify predictors of adverse outcomes.

Methods: This retrospective study was conducted by reviewing records of ED patients with pleural empyema admitted for VATS from January 2007 to June 2014.

Volume-regulated Cl current: contributions of distinct Cl channels and localized Ca signals.

The swelling-activated chloride current () is induced when a cell swells and plays a central role in maintaining cell volume in response to osmotic stress. The major contributor of is the volume-regulated anion channel (VRAC). Leucine-rich repeat containing 8A (LRRC8A; SWELL1) was recently identified as an essential component of VRAC, but the mechanisms of VRAC activation are still largely unknown; moreover, other Cl channels, such as anoctamin 1 (ANO1), were also suggested to contribute to .

Repressor element 1-silencing transcription factor drives the development of chronic pain states.

Chronic pain is an unmet clinical problem with vast individual, societal, and economic impact. Pathologic activity of the peripheral somatosensory afferents is one of the major drivers of chronic pain. This overexcitable state of somatosensory neurons is, in part, produced by the dysregulation of genes controlling neuronal excitability.