Dystrophin missense mutations alter focal adhesion tension and mechanotransduction.

Dystrophin is an essential muscle protein that contributes to cell membrane stability by mechanically linking the actin cytoskeleton to the extracellular matrix via an adhesion complex called the dystrophin-glycoprotein complex. The absence or impaired function of dystrophin causes muscular dystrophy. Focal adhesions (FAs) are also mechanosensitive adhesion complexes that connect the cytoskeleton to the extracellular matrix. However, the interplay between dystrophin and FA force transmission has not been investigated. Using a vinculin-based bioluminescent tension sensor, we measured FA tension in transgenic C2C12 myoblasts expressing wild-type (WT) dystrophin, a nonpathogenic single nucleotide polymorphism (SNP) (I232M), or two missense mutations associated with Duchenne (L54R), or Becker muscular dystrophy (L172H). Our data revealed cross talk between dystrophin and FAs, as the expression of WT or I232M dystrophin increased FA tension compared to dystrophin-less nontransgenic myoblasts. In contrast, the expression of L54R or L172H did not increase FA tension, indicating that these disease-causing mutations compromise the mechanical function of dystrophin as an FA allosteric regulator. Decreased FA tension caused by these mutations manifests as defective migration, as well as decreased Yes-associated protein 1 (YAP) activation, possibly by the disruption of the ability of FAs to transmit forces between the extracellular matrix and cytoskeleton. Our results indicate that dystrophin influences FA tension and suggest that dystrophin disease-causing missense mutations may disrupt a cellular tension-sensing pathway in dystrophic skeletal muscle.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

Schwann cell stimulation induces functional and structural changes in peripheral nerves.

Signal propagation is the essential function of nerves. Lysophosphatidic acid 18:1 (LPA) allows the selective stimulation of calcium signaling in Schwann cells but not neurons. Here, the time course of slowing and amplitude reduction on compound action potentials due to LPA exposure was observed in myelinated and unmyelinated fibers of the mouse, indicating a clear change of axonal function. Teased nerve fiber imaging showed that Schwann cell activation is also present in axon-attached Schwann cells in freshly isolated peripheral rat nerves. The LPA receptor 1 was primarily localized at the cell extensions in isolated rat Schwann cells, suggesting a role in cell migration. Structural investigation of rat C-fibers demonstrated that LPA leads to an evagination of the axons from their Schwann cells. In A-fibers, the nodes of Ranvier appeared unchanged, but the Schmidt-Lanterman incisures were shortened and myelination reduced. The latter might increase leak current, reducing the potential spread to the next node of Ranvier and explain the changes in conduction velocity. The observed structural changes provide a plausible explanation for the functional changes in myelinated and unmyelinated axons of peripheral nerves and the reported sensory sensations such as itch and pain.

EEG-based sensory testing reveals altered nociceptive processing in elite endurance athletes.

Increased exercise loads, as observed in elite athletes, seem to modulate the subjective pain perception in healthy subjects. The combination of electroencephalography (EEG) and standardized noxious stimulation can contribute to an objective assessment of the somatosensory stimulus processing. We assessed the subjective pain ratings and the electroencephalogram (EEG)-based response after standardized noxious mechanical and thermal stimuli as well as during conditioned pain modulation (CPM) in 26 elite endurance athletes and compared them to 26 recreationally active controls. Elite endurance athletes had consistently stronger somatosensory responses in the EEG to both mechanical and thermal noxious stimuli than the control group. We observed no significant group differences in the subjective pain ratings, which may have been influenced by our statistics and choice of stimuli. The CPM testing revealed that our conditioning stimulus modulated the subjective pain perception only in the control group, whereas the EEG indicated a modulatory effect of the conditioning stimulus on the spectral response only in the athletes group. We conclude that a higher activation in the cortical regions that process nociceptive information may either be an indicator for central sensitization or an altered stimulus salience in the elite endurance athletes' group. Our findings from our CPM testing were limited by our methodology. Further longitudinal studies are needed to examine if exercise-induced changes in the somatosensory system might have a critical impact on the long-term health of athletes.

Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.

Pathogenic variants in SPAST, the gene coding for spastin, are the single most common cause of hereditary spastic paraplegia, a progressive motor neuron disease. Spastin regulates key cellular functions, including microtubule-severing and endoplasmic reticulum-morphogenesis. However, it remains unclear how alterations in these cellular functions due to SPAST pathogenic variants result in motor neuron dysfunction. Since spastin influences both microtubule network and endoplasmic reticulum structure, we hypothesized that spastin is necessary for the regulation of Ca2+ homeostasis via store-operated calcium entry. Here, we show that the lack of spastin enlarges the endoplasmic reticulum and reduces store-operated calcium entry. In addition, elevated levels of different spastin variants induced clustering of STIM1 within the endoplasmic reticulum, altered the transport of STIM1 to the plasma membrane and reduced store-operated calcium entry, which could be rescued by exogenous expression of STIM1. Importantly, store-operated calcium entry was strongly reduced in induced pluripotent stem cell-derived neurons from hereditary spastic paraplegia patients with pathogenic variants in SPAST resulting in spastin haploinsufficiency. These neurons developed axonal swellings in response to lack of spastin. We were able to rescue both store-operated calcium entry and axonal swellings in SPAST patient neurons by restoring spastin levels, using CRISPR/Cas9 to correct the pathogenic variants in SPAST. These findings demonstrate that proper amounts of spastin are a key regulatory component for store-operated calcium entry mediated Ca2+ homeostasis and suggest store-operated calcium entry as a disease relevant mechanism of spastin-linked motor neuron disease.

TRPA1 as Target in Myocardial Infarction.

Transient receptor potential cation channel subfamily A member 1 (TRPA1), an ion channel primarily expressed on sensory neurons, can be activated by substances occurring during myocardial infarction. Aims were to investigate whether activation, inhibition, or absence of TRPA1 affects infarcts and to explore underlying mechanisms. In the context of myocardial infarction, rats received a TRPA1 agonist, an antagonist, or vehicle at different time points, and infarct size was assessed. Wild type and TRPA1 knockout mice were also compared in this regard. In vitro, sensory neurons were co-cultured with cardiomyocytes and subjected to a model of ischemia-reperfusion. Although there was a difference between TRPA1 activation or inhibition in vivo, no experimental group was different to control animals in infarct size, which also applies to animals lacking TRPA1. In vitro, survival probability of cardiomyocytes challenged by ischemia-reperfusion increased from 32.8% in absence to 45.1% in presence of sensory neurons, which depends, at least partly, on TRPA1. This study raises doubts about whether TRPA1 is a promising target to reduce myocardial damage within a 24 h period. The results are incompatible with relevant enlargements of infarcts by TRPA1 activation or inhibition, which argues against adverse effects when TRPA1 is targeted for other indications.

Hip Muscle Strength, Range of Motion, and Functional Performance in Young Elite Male Australian Football Players.

CONTEXT: Hip and groin injuries are common in field sports such as football, with measurement of hip strength and range of motion (ROM) recommended for assessment of these conditions. We aimed to report hip strength, hip ROM, and functional task performance in young elite Australian football athletes. DESIGN: Cross-sectional study. METHODS: Fifty-eight newly drafted Australian Football League athletes completed hip abduction, adduction, internal rotation, external rotation, and flexion strength testing with an adjustable stabilized or hand-held dynamometer. Hip internal rotation and external rotation, bent knee fall out, and ankle dorsiflexion ROM were also measured. Players completed hop for distance, side bridge, and star excursion balance functional tests. We compared findings between the dominant and nondominant limbs. RESULTS: We found small deficits unlikely to be clinically meaningful in the dominant limb for hip abduction and adduction strength, and a small deficit in the nondominant limb for external rotation strength and side bridge time. Athletes had lower hip internal rotation (mean difference 2.56°; 95% confidence interval, 0.87 to 4.26) and total rotation ROM (2.03°; 95% confidence interval, 0.06 to 4.01) on the dominant limb. CONCLUSIONS: There were no meaningful differences between dominant and nondominant limbs for hip strength, ROM, or functional tests. Our results may be used for benchmarking young male Australian football athletes when targeting optimal strength and returning from injury.

Nobel somatosensations and pain.

The Nobel prices 2021 for Physiology and Medicine have been awarded to David Julius and Ardem Patapoutian "for their discoveries of receptors for temperature and touch", TRPV1 and PIEZO1/2. The present review tells the past history of the capsaicin receptor, covers further selected TRP channels, TRPA1 in particular, and deals with mechanosensitivity in general and mechanical hyperalgesia in particular. Other achievements of the laureates and translational aspects of their work are shortly treated.

SAFit2 reduces neuroinflammation and ameliorates nerve injury-induced neuropathic pain.

BACKGROUND: Neuropathic pain is experienced worldwide by patients suffering from nerve injuries, infectious or metabolic diseases or chemotherapy. However, the treatment options are still limited because of low efficacy and sometimes severe side effects. Recently, the deficiency of FKBP51 was shown to relieve chronic pain, revealing FKBP51 as a potential therapeutic target. However, a specific and potent FKBP51 inhibitor was not available until recently which hampered targeting of FKBP51. METHODS: In this study, we used the well-established and robust spared nerve injury model to analyze the effect of SAFit2 on nerve injury-induced neuropathic pain and to elucidate its pharmacodynamics profile. Therefore, the mice were treated with 10 mg/kg SAFit2 after surgery, the mice behavior was assessed over 21 days and biochemical analysis were performed after 14 and 21 days. Furthermore, the impact of SAFit2 on sensory neurons and macrophages was investigated in vitro. RESULTS: Here, we show that the FKBP51 inhibitor SAFit2 ameliorates nerve injury-induced neuropathic pain in vivo by reducing neuroinflammation. SAFit2 reduces the infiltration of immune cells into neuronal tissue and counteracts the increased NF-κB pathway activation which leads to reduced cytokine and chemokine levels in the DRGs and spinal cord. In addition, SAFit2 desensitizes the pain-relevant TRPV1 channel and subsequently reduces the release of pro-inflammatory neuropeptides from sensory neurons. CONCLUSIONS: SAFit2 ameliorates neuroinflammation and counteracts enhanced neuronal activity after nerve injury leading to an amelioration of nerve injury-induced neuropathic pain. Based on these findings, SAFit2 constitutes as a novel and promising drug candidate for the treatment of nerve injury-induced neuropathic pain.

The role of petal transpiration in floral humidity generation.

MAIN CONCLUSION: Using petrolatum gel as an antitranspirant on the flowers of California poppy and giant bindweed, we show that transpiration provides a large contribution to floral humidity generation. Floral humidity, an area of elevated humidity in the headspace of flowers, is believed to be produced predominantly through a combination of evaporation of liquid nectar and transpirational water loss from the flower. However, the role of transpiration in floral humidity generation has not been directly tested and is largely inferred by continued humidity production when nectar is removed from flowers. We test whether transpiration contributes to the floral humidity generation of two species previously identified to produce elevated floral humidity, Calystegia silvatica and Eschscholzia californica. Floral humidity production of flowers that underwent an antitranspirant treatment, petrolatum gel which blocks transpiration from treated tissues, is compared to flowers that did not receive such treatments. Gel treatments reduced floral humidity production to approximately a third of that produced by untreated flowers in C. silvatica, and half of that in E. californica. This confirms the previously untested inferences that transpiration has a large contribution to floral humidity generation and that this contribution may vary between species.

A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice.

BACKGROUND: Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions. OBJECTIVES: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. METHODS: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. RESULTS: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. CONCLUSION: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions.

Analgesic Action of Acetaminophen via Kv7 Channels.

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

Bumblebees can detect floral humidity.

Floral humidity, a region of elevated humidity in the headspace of the flower, occurs in many plant species and may add to their multimodal floral displays. So far, the ability to detect and respond to floral humidity cues has been only established for hawkmoths when they locate and extract nectar while hovering in front of some moth-pollinated flowers. To test whether floral humidity can be used by other more widespread generalist pollinators, we designed artificial flowers that presented biologically relevant levels of humidity similar to those shown by flowering plants. Bumblebees showed a spontaneous preference for flowers that produced higher floral humidity. Furthermore, learning experiments showed that bumblebees are able to use differences in floral humidity to distinguish between rewarding and non-rewarding flowers. Our results indicate that bumblebees are sensitive to different levels of floral humidity. In this way floral humidity can add to the information provided by flowers and could impact pollinator behaviour more significantly than previously thought.

Acidified Nitrite Contributes to the Antitumor Effect of Cold Atmospheric Plasma on Melanoma Cells.

Cold atmospheric plasma (CAP) is partially ionized gas near room temperature with previously reported antitumor effects. Despite extensive research and growing interest in this technology, active components and molecular mechanisms of CAP are not fully understood to date. We used Raman spectroscopy and colorimetric assays to determine elevated nitrite and nitrate levels after treatment with a MiniFlatPlaster CAP device. Previously, we demonstrated CAP-induced acidification. Cellular effects of nitrite and strong extracellular acidification were assessed using live-cell imaging of intracellular Ca2+ levels, cell viability analysis as well as quantification of p21 and DNA damage. We further characterized these observations by analyzing established molecular effects of CAP treatment. A synergistic effect of nitrite and acidification was found, leading to strong cytotoxicity in melanoma cells. Interestingly, protein nitration and membrane damage were absent after treatment with acidified nitrite, thereby challenging their contribution to CAP-induced cytotoxicity. Further, phosphorylation of ERK1/2 was increased after treatment with both acidified nitrite and indirect CAP. This study characterizes the impact of acidified nitrite on melanoma cells and supports the importance of RNS during CAP treatment. Further, it defines and evaluates important molecular mechanisms that are involved in the cancer cell response to CAP.

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

A Human TRPA1-Specific Pain Model.

The cation channel transient receptor potential ankyrin 1 (TRPA1) plays an important role in sensing potentially hazardous substances. However, TRPA1 species differences are substantial and limit translational research. TRPA1 agonists tested previously in humans also have other targets. Therefore, the sensation generated by isolated TRPA1 activation in humans is unknown. The availability of 2-chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)-N-(3-methoxypropyl)-acetamide (JT010), a potent and specific TRPA1 agonist, allowed us to explore this issue. To corroborate the specificity of JT010, it was investigated whether the TRPA1 antagonist (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-penten-3-one oxime (A-967079) abolishes JT010-elicited pain. Sixteen healthy volunteers of both sexes rated pain due to intraepidermal injections of different concentrations and combinations of the substances. The study design was a double-blind crossover study. All subjects received all types of injections, including a placebo without substances. Injections of the TRPA1 agonist dose-dependently caused pain with a half-maximal effective concentration of 0.31 µm Coinjection of A-967079 dose-dependently reduced and at a high concentration abolished JT010-induced pain. Quantification of JT010 by HPLC showed that a substantial part is adsorbed when in contact with polypropylene surfaces, but that this was overcome by handling in glass vials and injection using glass syringes. Isolated TRPA1 activation in humans causes pain. Thus, intradermal JT010 injection can serve as a tool to validate new TRPA1 antagonists concerning target engagement. More importantly, TRPA1-specific tools allow quantification of the TRPA1-dependent component in physiology and pathophysiology.SIGNIFICANCE STATEMENT This study showed that activation of the ion channel transient receptor potential ankyrin 1 (TRPA1) alone indeed suffices to elicit pain in humans, independent of other receptors previously found to be involved in pain generation. The newly established TRPA1-specific pain model allows different applications. First, it can be tested whether diseases are associated with compromised or exaggerated TRPA1-dependent painful sensations in the skin. Second, it can be investigated whether a new, possibly systemically applied drug directed against TRPA1 engages its target in humans. Further, the general possibility of quantitative inhibition of TRPA1 allows identification of the TRPA1-dependent disease component, given that the substance reaches its target. This contributes to a better understanding of pathophysiology, can lay the basis for new therapeutic approaches, and can bridge the gap between preclinical research and clinical trials.

Afferent renal innervation in anti-Thy1.1 nephritis in rats.

Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin gene-related peptide (CGRP). We tested the hypothesis that increased afferent and efferent renal nerve activity occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), and animals were investigated neurophysiologically, electrophysiologically, and pathomorphologically 6 days later. Nephritic rats exhibited proteinuria (169.3 ± 10.2 mg/24 h) with increased efferent renal nerve activity (14.7 ± 0.9 bursts/s vs. control 11.5 ± 0.9 bursts/s, n = 11, P < 0.05). However, afferent renal nerve activity (in spikes/s) decreased in nephritis (8.0 ± 1.8 Hz vs. control 27.4 ± 4.1 Hz, n = 11, P < 0.05). In patch-clamp recordings, neurons with renal afferents from nephritic rats showed a lower frequency of high activity following electrical stimulation (43.4% vs. 66.4% in controls, P < 0.05). In vitro assays showed that renal tissue from nephritic rats exhibited increased CGRP release via spontaneous (14 ± 3 pg/mL vs. 6.8 ± 2.8 pg/ml in controls, n = 7, P < 0.05) and stimulated mechanisms. In nephritic animals, marked infiltration of macrophages in the interstitium (26 ± 4 cells/mm2) and glomeruli (3.7 ± 0.6 cells/glomerular cross-section) occurred. Pretreatment with the CGRP receptor antagonist CGRP8-37 reduced proteinuria, infiltration, and proliferation. In nephritic rats, it can be speculated that afferent renal nerves lose their ability to properly control efferent sympathetic nerve activity while influencing renal inflammation through increased CGRP release.

Lysophosphatidic acid activates satellite glia cells and Schwann cells.

Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.

TRPA1: a molecular view.

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed in pain-sensing neurons and other tissues and has become a major target in the development of novel pharmaceuticals. A remarkable feature of the channel is its long list of activators, many of which we are exposed to in daily life. Many of these agonists induce pain and inflammation, making TRPA1 a major target for anti-inflammatory and analgesic therapies. Studies in human patients and in experimental animals have confirmed an important role for TRPA1 in a number of pain conditions. Over the recent years, much progress has been made in elucidating the molecular structure of TRPA1 and in discovering binding sites and modulatory sites of the channel. Because the list of published mutations and important molecular sites is steadily growing and because it has become difficult to see the forest for the trees, this review aims at summarizing the current knowledge about TRPA1, with a special focus on the molecular structure and the known binding or gating sites of the channel.

Cross-modal transfer in visual and nonvisual cues in bumblebees.

Bumblebees Bombus terrestris are good at learning to distinguish between patterned flowers. They can differentiate between flowers that differ only in their patterning of scent, surface texture, temperature, or electrostatic charge, in addition to visual patterns. As recently shown, bumblebees trained to discriminate between nonvisual scent patterns can transfer this learning to visually patterned flowers that show similar spatial patterning to the learnt scent patterns. Bumblebees can, therefore, transfer learnt patterns between different sensory modalities, without needing to relearn them. We used differential conditioning techniques to explore whether cross-modal transfer of learnt patterns also occurred between visual and temperature patterns. Bumblebees that successfully learnt to distinguish rewarding and unrewarding temperature patterns did not show any preferences for the corresponding unlearnt visual pattern. Similarly, bumblebees that learnt visual patterns did not transfer these to temperature patterns, suggesting that they are unable to transfer learning of temperature and visual patterns. We discuss how cross-modality pattern learning may be limited to modalities that have potentially strong neurological links, such as the previously demonstrated transfer between scent and visual patterns.