The Journal of physiology
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The Journal of physiology · Feb 2012
Inhibition of voltage-gated proton channels by local anaesthetics in GMI-R1 rat microglia.
Voltage-gated proton channels play crucial roles during the respiratory burst in phagocytes, such as microglia. As local anaesthetics have a variety of anti-inflammatory properties, including inhibition of phagocytosis, they may act on the proton channels. Most local anaesthetics are tertiary amines and may affect proton channels through modification of pH(i) as weak bases. ⋯ Furthermore, chemiluminescence measurement proved that both anaesthetics inhibited production of reactive oxygen species by the cells. In conclusion, lidocaine and bupivacaine inhibit proton channels primarily by the weak base mechanism via an increase in pH(i). This is a novel mechanism underlying actions of local anaesthtics.
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The Journal of physiology · Feb 2012
Controlled Clinical TrialThe early release of planned movement by acoustic startle can be delayed by transcranial magnetic stimulation over the motor cortex.
Previous studies have shown that preplanned movements can be rapidly released when a startling acoustic stimulus (SAS) is presented immediately prior to, or coincident with, the imperative signal to initiate movement. Based on the short latency of the onset of muscle activity (typically in less than 90 ms) and the frequent co-expression of startle responses in the neck and eye muscles, it has been proposed that the release of planned movements by a SAS is mediated by subcortical, possibly brainstem, pathways. However, a role for cortical structures in mediating these responses cannot be ruled out based on timing arguments alone. ⋯ The early release of movement by a SAS was significantly delayed (P < 0.001, average delay = 35.0 ± 12.9 ms) when TMS(SAS) and SAS were presented concurrently. This delay could not be explained by a prolonged suppression of motor unit activity at the spinal level. These findings provide evidence that the release of targeted ballistic wrist movements by SAS is mediated, in part, by a fast conducting transcortical pathway via the primary motor cortex.
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The Journal of physiology · Feb 2012
Sound-evoked network calcium transients in mouse auditory cortex in vivo.
Population calcium signals generated by the action potential activity of local clusters of neurons have been recorded in the auditory cortex of mice using an optical fibre-based approach. These network calcium transients (NCaTs) occurred spontaneously as well as in response to sound stimulation. Two-photon calcium imaging experiments suggest that neurons and neuropil contribute about equally to the NCaT. ⋯ The slow NCaTs were correlated with global ‘up states' recorded with epidural potentials, and sound presented during an epidural ‘down state' triggered a calcium transient that was associated with an epidural ‘up state'. Essentially indistinguishable calcium transients were evoked by optogenetic activation of local clusters of layer 5 pyramidal neurons in the auditory cortex, indicating that these neurons play an important role in the generation of the calcium signal. Taken together, our results identify sound-evoked slow NCaTs as an integral component of neuronal signalling in the mouse auditory cortex, reflecting the prolonged neuronal activity of local clusters of neurons that can be activated even by brief stimuli.
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The Journal of physiology · Feb 2012
VAMP8 is a vesicle SNARE that regulates mucin secretion in airway goblet cells.
Mucin secretion is an innate defence mechanism, which is noxiously upregulated in obstructive lung diseases (e.g. chronic obstructive pulmonary disease (COPD), cystic fibrosis and asthma). Mucin granule exocytosis is regulated by specific protein complexes, but the SNARE exocytotic core has not been defined in airway goblet cells. In this study, we identify VAMP8 as one of the SNAREs regulating mucin granule exocytosis. ⋯ Importantly, in VAMP8 knock-out (KO) mice with IL-13-induced mucous metaplasia, mucin content in the bronchoalveolar lavage (BAL) and ATP-stimulated mucin secretion in the trachea were reduced compared to WT-matched littermates. Our data indicate that VAMP8 is an essential SNARE in airway mucin granule exocytosis. Reduction of VAMP8 activity/expression may provide a novel therapeutic target to ameliorate airway mucus obstruction in lung diseases.