The Experts below are selected from a list of 9516 Experts worldwide ranked by ideXlab platform
Miriam B Goodman - One of the best experts on this subject based on the ideXlab platform.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
Nick J Spencer - One of the best experts on this subject based on the ideXlab platform.
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enteric nervous system Sensory Transduction neural circuits and gastrointestinal motility
Nature Reviews Gastroenterology & Hepatology, 2020Co-Authors: Nick J Spencer, Hongzhen HuAbstract:The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate Sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes Sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanoTransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. ChemoSensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic Sensory neurons in the ENS detect and respond to Sensory stimuli and how these mechanisms differ from extrinsic Sensory nerve endings in the gut that underlie the gut–brain axis. The enteric nervous system (ENS) is essential for life and controls the function of the gastrointestinal tract. Here, an overview of Sensory Transduction and neural circuits in the ENS is provided, yielding insights into the generation of gastrointestinal motility.
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enteric nervous system Sensory Transduction neural circuits and gastrointestinal motility
Nature Reviews Gastroenterology & Hepatology, 2020Co-Authors: Nick J SpencerAbstract:The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate Sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes Sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanoTransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. ChemoSensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic Sensory neurons in the ENS detect and respond to Sensory stimuli and how these mechanisms differ from extrinsic Sensory nerve endings in the gut that underlie the gut-brain axis.
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imaging activation of peptidergic spinal afferent varicosities within visceral organs using novel cgrpα mcherry reporter mice
American Journal of Physiology-gastrointestinal and Liver Physiology, 2016Co-Authors: Nick J Spencer, Julian Sorensen, Lee Travis, Lukasz Wiklendt, M Costa, Timothy J HibberdAbstract:Until now, all recordings from spinal afferent neurons have been made outside their target peripheral organ, which is not where Sensory Transduction takes place. This study shows that transgenic CG...
Robert Ohagan - One of the best experts on this subject based on the ideXlab platform.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
Jeffrey R. Holt - One of the best experts on this subject based on the ideXlab platform.
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probing the structure and function of tmc1 in Sensory hair cells using mutagenesis and cysteine modification
Biophysical Journal, 2015Co-Authors: Xiaoping Liu, Yukako Asai, Kiyoto Kurima, Andrew J Griffith, Bifeng Pan, Jeffrey R. HoltAbstract:Transmembrane channel-like genes 1 and 2 (Tmc1 and Tmc2) have recently been implicated as components of the Sensory Transduction channel in mammalian hair cells. Mice deficient in both Tmc1 and Tmc2 have complete loss of hearing and balance function and lack Sensory Transduction, despite intact hair bundles and tip-links (Kawashima et al., 2011). Mice that express only TMC1 or TMC2 have distinct single-channel conductances and calcium selectivity. A methionine-to-lysine substitution at position 412 in TMC1 reduces the single-channel current amplitude and calcium permeability of Transduction (Pan et al., 2013). These results suggest that TMCs participate as essential components of the Sensory Transduction channel in auditory and vestibular hair cells, but their exact role is not yet clear. They may form a vestibule at the mouth of the pore, the pore of the ion channel itself or both (Holt et al., 2014). Alternatively, TMCs may function as non-essential accessory subunits (Beurg et al., 2014). Progress toward understanding the structure and function of TMC proteins has been limited by the lack of homology to known genes or domains (Kurima et al., 2003); the low quantity of native protein (50-100 functional channels/cell); and poor membrane localization in heterologous cells. To circumvent these limitations, we combined electrophysiological recording with mutagenesis and cysteine modification in native hair cells. To probe TMC1 structure and function, mutant Tmc1 sequences were introduced, via viral transfection, into organotypic cultures harvested from Tmc1/Tmc2 doubly-deficient mice. We find that the mutant constructs restore sensitivity to hair bundle deflections in virally-transfected hair cells and that acute application of cysteine modification reagents alters the biophysical properties of Sensory Transduction within seconds. The data further support a direct role for TMC1 in Sensory Transduction in mammalian hair cells.
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tmc1 and tmc2 are components of the mechanoTransduction channel in hair cells of the mammalian inner ear
Neuron, 2013Co-Authors: Gwenaelle S G Geleoc, Yoshiyuki Kawashima, Yukako Asai, Geoffrey C Horwitz, Kiyoto Kurima, Kotaro Ishikawa, Andrew J Griffith, Jeffrey R. HoltAbstract:Summary Sensory Transduction in auditory and vestibular hair cells requires expression of transmembrane channel-like ( Tmc ) 1 and 2 genes, but the function of these genes is unknown. To investigate the hypothesis that TMC1 and TMC2 proteins are components of the mechanosensitive ion channels that convert mechanical information into electrical signals, we recorded whole-cell and single-channel currents from mouse hair cells that expressed Tmc1, Tmc2 , or mutant Tmc1 . Cells that expressed Tmc2 had high calcium permeability and large single-channel currents, while cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents. Cells that expressed Tmc1 and Tmc2 had a broad range of single-channel currents, suggesting multiple heteromeric assemblies of TMC subunits. The data demonstrate TMC1 and TMC2 are components of hair cell Transduction channels and contribute to permeation properties. Gradients in TMC channel composition may also contribute to variation in Sensory Transduction along the tonotopic axis of the mammalian cochlea.
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Development and regeneration of Sensory Transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010Co-Authors: Andrea Lelli, Piotr Kazmierczak, Yoshiyuki Kawashima, Jeffrey R. HoltAbstract:Tip links are extracellular filaments that connect pairs of hair cell stereocilia and convey tension to mechanosensitive channels. Recent evidence suggests that tip links are formed by calcium-dependent interactions between the N-terminal domains of cadherin-23 (CDH23) and protocadherin-15 (PCDH15). Mutations in either CDH23 or PCDH15 cause deafness in mice and humans, indicating the molecules are required for normal inner ear function. However, there is little physiological evidence to support a direct role for CDH23 and PCDH15 in hair cell mechanoTransduction. To investigate the contributions of CDH23 and PCDH15 to mechanoTransduction and tip-link formation, we examined outer hair cells of mouse cochleas during development and after chemical disruption of tip links. We found that tip links and mechanoTransduction with all the qualitative properties of mature Transduction recovered within 24 h after disruption. To probe tip-link formation, we measured Transduction currents after extracellular application of recombinant CDH23 and PCDH15 fragments, which included putative interaction domains (EC1). Both fragments inhibited development and regeneration of Transduction but did not disrupt Transduction in mature cells. PCDH15 fragments that carried a mutation in EC1 that causes deafness in humans did not inhibit Transduction development or regeneration. Immunolocalization revealed wild-type fragments bound near the tips of hair cell stereocilia. Scanning electron micrographs revealed that hair bundles exposed to fragments had a reduced number of linkages aligned along the morphological axis of sensitivity of the bundle. Together, the data provide direct evidence implicating CDH23 and PCDH15 proteins in the formation of tip links during development and regeneration of mechanoTransduction.
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tonotopic gradient in the developmental acquisition of Sensory Transduction in outer hair cells of the mouse cochlea
Journal of Neurophysiology, 2009Co-Authors: Andrea Lelli, Jeffrey R. Holt, Yukako Asai, Andrew Forge, Gwenaelle S G GeleocAbstract:Inner ear hair cells are exquisite mechanosensors that transduce nanometer scale deflections of their Sensory hair bundles into electrical signals. Several essential elements must be precisely assembled during development to confer the unique structure and function of the mechanoTransduction apparatus. Here we investigated the functional development of the Transduction complex in outer hair cells along the length of mouse cochlea acutely excised between embryonic day 17 (E17) and postnatal day 8 (P8). We charted development of the stereociliary bundle using scanning electron microscopy; FM1-43 uptake, which permeates hair cell Transduction channels, mechanoTransduction currents evoked by rapid hair bundle deflections, and mRNA expression of possible components of the Transduction complex. We demonstrated that uptake of FM1-43 first occurred in the basal portion of the cochlea at P0 and progressed toward the apex over the subsequent week. Electrophysiological recordings obtained from 234 outer hair cells between E17 and P8 from four cochlear regions revealed a correlation between the pattern of FM1-43 uptake and the acquisition of mechanoTransduction. We found a spatiotemporal gradient in the properties of Transduction including onset, amplitude, operating range, time course, and extent of adaptation. We used quantitative RT–PCR to examine relative mRNA expression of several hair cell myosins and candidate tip-link molecules. We found spatiotemporal expression patterns for mRNA that encodes cadherin 23, protocadherin 15, myosins 3a, 7a, 15a, and PMCA2 that preceded the acquisition of Transduction. The spatiotemporal expression patterns of myosin 1c and PMCA2 mRNA were correlated with developmental changes in several properties of mechanoTransduction.
Martin Chalfie - One of the best experts on this subject based on the ideXlab platform.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
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the mec 4 deg enac channel of caenorhabditis elegans touch receptor neurons transduces mechanical signals
Nature Neuroscience, 2005Co-Authors: Robert Ohagan, Martin Chalfie, Miriam B GoodmanAbstract:Transformation of mechanical energy into ionic currents is essential for touch, hearing and nociception. Although DEG/ENaC proteins are believed to form Sensory mechanoTransduction channels, the evidence for this role remains indirect. By recording from C. elegans touch receptor neurons in vivo, we found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na+ and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, these neurons depolarized with both positive and negative changes in external force but not with sustained force. Null mutations in the DEG/ENaC gene mec-4 and in the accessory ion channel subunit genes mec-2 and mec-6 eliminated MRCs. In contrast, the genetic elimination of touch neuron–specific microtubules reduced, but did not abolish, MRCs. Our findings link the application of external force to the activation of a molecularly defined metazoan Sensory Transduction channel.
