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Barry W. Ache - One of the best experts on this subject based on the ideXlab platform.
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Inhibitory signaling in mammalian Olfactory Transduction potentially mediated by Gαo
Molecular and cellular neurosciences, 2020Co-Authors: Elizabeth A. Corey, Kirill Ukhanov, Yuriy V. Bobkov, Jeremy C. Mcintyre, Jeffrey R. Martens, Barry W. AcheAbstract:Olfactory GPCRs (ORs) in mammalian Olfactory receptor neurons (ORNs) mediate excitation through the Gαs family member Gαolf. Here we tentatively associate a second G protein, Gαo, with inhibitory signaling in mammalian Olfactory Transduction by first showing that odor evoked phosphoinositide 3-kinase (PI3K)-dependent inhibition of signal Transduction is absent in the native ORNs of mice carrying a conditional OMP-Cre based knockout of Gαo. We then identify an OR from native rat ORNs that are activated by octanol through cyclic nucleotide signaling and inhibited by citral in a PI3K-dependent manner. We show that the OR activates cyclic nucleotide signaling and PI3K signaling in a manner that reflects its functionality in native ORNs. Our findings lay the groundwork to explore the interesting possibility that ORs can interact with two different G proteins in a functionally identified, ligand-dependent manner to mediate opponent signaling in mature mammalian ORNs.
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Comparative Olfactory Transduction
Chemosensory Transduction, 2016Co-Authors: Elizabeth A. Corey, Barry W. AcheAbstract:Animals use Olfactory receptors to detect chemical cues at a distance from the source to mediate diverse behavioral responses. Although olfaction is typically considered in the context of terrestrial organisms, aquatic organisms use it to detect water-soluble compounds for the same purposes with basically the same neural machinery. Despite the differences in the signal Transduction pathways associated with different Olfactory receptor types, the animals that use them all exist in the same Olfactory world with the same challenge of identifying behaviorally relevant odors. Given the fundamental requirements of olfaction, such as those for sensitivity and speed to allow for rapid behavioral responses, substantial similarities resulting from evolutionary convergence have occurred. Comparative study of the signal Transduction mechanisms in a variety of animal models therefore can help us to identify the important functional characteristics that define olfaction.
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The Na+/Ca2+ exchanger inhibitor, KB-R7943, blocks a nonselective cation channel implicated in chemosensory Transduction.
Journal of neurophysiology, 2008Co-Authors: Adeline Pezier, Yuriy V. Bobkov, Barry W. AcheAbstract:The mechanism(s) of Olfactory Transduction in invertebrates remains to be fully understood. In lobster Olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presump...
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Calcium sensitivity of a sodium-activated nonselective cation channel in lobster Olfactory receptor neurons.
Journal of neurophysiology, 2003Co-Authors: Yuriy V. Bobkov, Barry W. AcheAbstract:We report that a Na+-activated nonselective cation channel described previously in lobster Olfactory neurons, in which phosphoinositide signaling mediates Olfactory Transduction, can also be activated by Ca2+. Ca2+ activates the channel in the presence of Na+, increasing the open probability of the channel with a K1/2 of 490 nM and a Hill coefficient of 1.3. Ca2+ also increases the sensitivity of the channel to Na+. In some cells, the same channel is Ca2+ insensitive in a cell-specific manner. The nonspecific activator of protein phosphatases, protamine, applied to the intracellular face of patches containing the channel irreversibly eliminates the sensitivity to Ca2+. This effect can be blocked by okadaic acid, a nonspecific blocker of protein phosphatases, and restored by the catalytic subunit of protein kinase A in the presence of MgATP. The Ca2+-sensitive form of the channel is predominantly expressed in the Transduction zone of the cells in situ. These findings imply that the Ca2+ sensitivity of the channel, and possibly its regulation by phosphorylation, play a role in Olfactory Transduction and help tie activation of the channel to the canonical phosphoinositide turnover pathway.
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Properties and Functional Role of a Sodium-Activated Nonselective Cation Channel in Lobster Olfactory Receptor Neurons
The Crustacean Nervous System, 2002Co-Authors: Asylbek B. Zhainazarov, Richard E. Doolin, Barry W. AcheAbstract:Research on lobster Olfactory receptor cells has implicated a novel sodium-activated nonselective cation channel in Olfactory Transduction. In addition to providing some of the first evidence for a functional role for sodium-activated channels, these studies provide a possible explanation as to how the sensitivity of these channels to sodium could be much greater in intact cells than in excised patches.
Anna Menini - One of the best experts on this subject based on the ideXlab platform.
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The long tale of the calcium activated Cl- channels in Olfactory Transduction.
Channels (Austin Tex.), 2017Co-Authors: Michele Dibattista, Anna Menini, Simone Pifferi, Anna Boccaccio, Johannes ReisertAbstract:Ca2+-activated Cl- currents have been implicated in many cellular processes in different cells, but for many years, their molecular identity remained unknown. Particularly intriguing are Ca2+-activated Cl- currents in Olfactory Transduction, first described in the early 90s. Well characterized electrophysiologically, they carry most of the odorant-induced receptor current in the cilia of Olfactory sensory neurons (OSNs). After many attempts to determine their molecular identity, TMEM16B was found to be abundantly expressed in the cilia of OSNs in 2009 and having biophysical properties like those of the native Olfactory channel. A TMEM16B knockout mouse confirmed that TMEM16B was indeed the Olfactory Cl- channel but also suggested a limited role in Olfactory physiology and behavior. The question then arises of what the precise role of TMEM16b in olfaction is. Here we review the long story of this channel and its possible roles.
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A Dynamical Feedback Model for Adaptation in the Olfactory Transduction Pathway
Biophysical journal, 2012Co-Authors: Giovanna De Palo, Anna Menini, Anna Boccaccio, Andrew Miri, Claudio AltafiniAbstract:Olfactory Transduction exhibits two distinct types of adaptation, which we denote multipulse and step adaptation. In terms of measured Transduction current, multipulse adaptation appears as a decrease in the amplitude of the second of two consecutive responses when the Olfactory neuron is stimulated with two brief pulses. Step adaptation occurs in response to a sustained steplike stimulation and is characterized by a return to a steady-state current amplitude close to the prestimulus value, after a transient peak. In this article, we formulate a dynamical model of the Olfactory Transduction pathway, which includes the kinetics of the CNG channels, the concentration of Ca ions flowing through them, and the Ca-complexes responsible for the regulation. Based on this model, a common dynamical explanation for the two types of adaptation is suggested. We show that both forms of adaptation can be well described using different time constants for the kinetics of Ca ions (faster) and the kinetics of the feedback mechanisms (slower). The model is validated on experimental data collected in voltage-clamp conditions using different techniques and animal species.
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Flash photolysis of caged compounds in the cilia of Olfactory sensory neurons.
Journal of visualized experiments : JoVE, 2011Co-Authors: Anna Boccaccio, Claudia Sagheddu, Anna MeniniAbstract:Photolysis of caged compounds allows the production of rapid and localized increases in the concentration of various physiologically active compounds1. Caged compounds are molecules made physiologically inactive by a chemical cage that can be broken by a flash of ultraviolet light. Here, we show how to obtain patch-clamp recordings combined with photolysis of caged compounds for the study of Olfactory Transduction in dissociated mouse Olfactory sensory neurons. The process of Olfactory Transduction (Figure 1) takes place in the cilia of Olfactory sensory neurons, where odorant binding to receptors leads to the increase of cAMP that opens cyclic nucleotide-gated (CNG) channels2. Ca entry through CNG channels activates Ca-activated Cl channels. We show how to dissociate neurons from the mouse Olfactory epithelium3 and how to activate CNG channels or Ca-activated Cl channels by photolysis of caged cAMP4 or caged Ca5. We use a flash lamp6,7 to apply ultraviolet flashes to the ciliary region to uncage cAMP or Ca while patch-clamp recordings are taken to measure the current in the whole-cell voltage-clamp configuration8-11.
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Anoctamin 2/TMEM16B: a calcium-activated chloride channel in Olfactory Transduction.
Experimental physiology, 2011Co-Authors: Simone Pifferi, Valentina Cenedese, Anna MeniniAbstract:In vertebrate Olfactory Transduction, a Ca(2+)-dependent Cl(-) efflux greatly amplifies the odorant response. The binding of odorants to receptors in the cilia of Olfactory sensory neurons activates a Transduction cascade that involves the opening of cyclic nucleotide-gated channels and the entry of Ca(2+) into the cilia. The Ca(2+) activates a Cl(-) current that, in the presence of a maintained elevated intracellular Cl(-) concentration, produces an efflux of Cl(-) ions and amplifies the depolarization. In this review, we summarize evidence supporting the hypothesis that anoctamin 2/TMEM16B is the main, or perhaps the only, constituent of the Ca(2+)-activated Cl(-) channels involved in Olfactory Transduction. Indeed, studies from several laboratories have shown that anoctamin 2/TMEM16B is expressed in the ciliary layer of the Olfactory epithelium, that there are remarkable functional similarities between currents in Olfactory sensory neurons and in HEK 293 cells transfected with anoctamin 2/TMEM16B, and that knockout mice for anoctamin 2/TMEM16B did not show any detectable Ca(2+)-activated Cl(-) current. Finally, we discuss the involvement of Ca(2+)-activated Cl(-) channels in the Transduction process of vomeronasal sensory neurons and the physiological role of these channels in olfaction.
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Odorant Detection and Discrimination in the Olfactory System
Lecture Notes in Electrical Engineering, 2011Co-Authors: Simone Pifferi, Anna MeniniAbstract:The Olfactory system excels in both discrimination and detection of odorants. In mammals, it reliably discriminates more than 3000 structurally diverse odorant molecules and has an amazingly high sensitivity that allows the detection of very low amounts of specific odorant molecules. In addition, the Olfactory system has the capability to adapt to ambient odorants, allowing the recognition of a broad range of stimuli. The discrimination among different odorants is achieved by using hundreds of receptors, activated with a combinatorial code. Olfactory Transduction uses a canonical second messenger system providing two critical attributes: amplification and high signal-to-noise characteristics, giving the system its remarkable detector capabilities. In this review, we present an introduction to the basic molecular mechanisms of Olfactory Transduction in Olfactory sensory neurons.
Johannes Reisert - One of the best experts on this subject based on the ideXlab platform.
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The functional relevance of Olfactory marker protein in the vertebrate Olfactory system: a never-ending story
Cell and Tissue Research, 2021Co-Authors: Michele Dibattista, Dolly Al Koborssy, Federica Genovese, Johannes ReisertAbstract:Olfactory marker protein (OMP) was first described as a protein expressed in Olfactory receptor neurons (ORNs) in the nasal cavity. In particular, OMP, a small cytoplasmic protein, marks mature ORNs and is also expressed in the neurons of other nasal chemosensory systems: the vomeronasal organ, the septal organ of Masera, and the Grueneberg ganglion. While its expression pattern was more easily established, OMP’s function remained relatively vague. To date, most of the work to understand OMP’s role has been done using mice lacking OMP. This mostly phenomenological work has shown that OMP is involved in sharpening the odorant response profile and in quickening odorant response kinetics of ORNs and that it contributes to targeting of ORN axons to the Olfactory bulb to refine the glomerular response map. Increasing evidence shows that OMP acts at the early stages of Olfactory Transduction by modulating the kinetics of cAMP, the second messenger of Olfactory Transduction. However, how this occurs at a mechanistic level is not understood, and it might also not be the only mechanism underlying all the changes observed in mice lacking OMP. Recently, OMP has been detected outside the nose, including the brain and other organs. Although no obvious logic has become apparent regarding the underlying commonality between nasal and extranasal expression of OMP, a broader approach to diverse cellular systems might help unravel OMP’s functions and mechanisms of action inside and outside the nose.
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Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017Co-Authors: Anna K. Talaga, Frederick N. Dong, Johannes Reisert, Haiqing ZhaoAbstract:Animals detect odorous chemicals through specialized Olfactory sensory neurons (OSNs) that transduce odorants into neural electrical signals. We identified a novel and evolutionarily conserved protein, cilia- and flagella-associated protein 69 (CFAP69), in mice that regulates Olfactory Transduction kinetics. In the Olfactory epithelium, CFAP69 is enriched in OSN cilia, where Olfactory Transduction occurs. Bioinformatic analysis suggests that a large portion of CFAP69 can form Armadillo-type α-helical repeats, which may mediate protein-protein interactions. OSNs lacking CFAP69, remarkably, displayed faster kinetics in both the on and off phases of electrophysiological responses at both the neuronal ensemble level as observed by electroolfactogram and the single-cell level as observed by single-cell suction pipette recordings. In single-cell analysis, OSNs lacking CFAP69 showed faster response integration and were able to fire APs more faithfully to repeated odor stimuli. Furthermore, both male and female mutant mice that specifically lack CFAP69 in OSNs exhibited attenuated performance in a buried food pellet test when a background of the same odor to the food pellet was present even though they should have better temporal resolution of coding Olfactory stimulation at the peripheral. Therefore, the role of CFAP69 in the Olfactory system seems to be to allow the Olfactory Transduction machinery to work at a precisely regulated range of response kinetics for robust Olfactory behavior.SIGNIFICANCE STATEMENT Sensory receptor cells are generally thought to evolve to respond to sensory cues as fast as they can. This idea is consistent with mutational analyses in various sensory systems, where mutations of sensory receptor cells often resulted in reduced response size and slowed response kinetics. Contrary to this idea, we have found that there is a kinetic "damper" present in the Olfactory Transduction cascade of the mouse that slows down the response kinetics and, by doing so, it reduces the peripheral temporal resolution in coding odor stimuli and allows for robust Olfactory behavior. This study should trigger a rethinking of the significance of the intrinsic speed of sensory Transduction and the pattern of the peripheral coding of sensory stimuli.
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The long tale of the calcium activated Cl- channels in Olfactory Transduction.
Channels (Austin Tex.), 2017Co-Authors: Michele Dibattista, Anna Menini, Simone Pifferi, Anna Boccaccio, Johannes ReisertAbstract:Ca2+-activated Cl- currents have been implicated in many cellular processes in different cells, but for many years, their molecular identity remained unknown. Particularly intriguing are Ca2+-activated Cl- currents in Olfactory Transduction, first described in the early 90s. Well characterized electrophysiologically, they carry most of the odorant-induced receptor current in the cilia of Olfactory sensory neurons (OSNs). After many attempts to determine their molecular identity, TMEM16B was found to be abundantly expressed in the cilia of OSNs in 2009 and having biophysical properties like those of the native Olfactory channel. A TMEM16B knockout mouse confirmed that TMEM16B was indeed the Olfactory Cl- channel but also suggested a limited role in Olfactory physiology and behavior. The question then arises of what the precise role of TMEM16b in olfaction is. Here we review the long story of this channel and its possible roles.
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perspectives on information and coding in mammalian sensory physiology response kinetics of Olfactory receptor neurons and the implications in Olfactory coding
The Journal of General Physiology, 2011Co-Authors: Johannes Reisert, Haiqing ZhaoAbstract:Olfaction begins with the detection of odorants by Olfactory receptor neurons (ORNs) in the nasal cavity. Olfactory Transduction is mediated by a G protein–coupled Transduction cascade culminating in the opening of the two Olfactory Transduction ion channels, the Olfactory CNG channel and the Ca2+-activated Cl− channel anoctamin 2 (Ano2), and ultimately action potential (AP) generation. The mechanisms that activate Olfactory Transduction have been understood quite well over the last two decades. Mechanisms of response adaptation, however, have actually become much less clear, with mechanisms previously thought to be important now suggested to play less significant roles, raising the question of which Transduction components are the target of adaptational feedback. Because ORNs are often stimulated rhythmically by the inhalation of odorants, fast response termination should be a prerequisite to adequately resolve the temporal aspect of the stimulus. Recent progress suggests that mechanisms that regulate ciliary Ca2+ transients dictate kinetics of Transduction termination. Ultimately, the question to answer is how ORNs code for “natural” stimuli in the behaving animal.
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Mechanisms of chloride uptake in frog Olfactory receptor neurons
Journal of Comparative Physiology A, 2011Co-Authors: Cristina Jaén, Mehmet Hakan Ozdener, Johannes ReisertAbstract:Odorant stimulation of Olfactory receptor neurons (ORNs) leads to the activation of a Ca^2+ permeable cyclic nucleotide-gated (CNG) channel followed by opening of an excitatory Ca^2+-activated Cl^− channel, which carries about 70% of the odorant-induced receptor current. This requires ORNs to have a [Cl^−]_i above the electrochemical equilibrium to render this anionic current excitatory. In mammalian ORNs, the Na^+-K^+-2Cl^− co-transporter 1 (NKCC1) has been characterized as the principal mechanism by which these neurons actively accumulate Cl^−. To determine if NKCC activity is needed in amphibian Olfactory Transduction, and to characterize its cellular location, we used the suction pipette technique to record from Rana pipiens ORNs. Application of bumetanide, an NKCC blocker, produced a 50% decrease of the odorant-induced current. Similar effects were observed when [Cl^−]_i was decreased by bathing ORNs in low Cl^− solution. Both manipulations reduced only the Cl^− component of the current. Application of bumetanide only to the ORN cell body and not to the cilia decreased the current by again about 50%. The results show that NKCC is required for amphibian Olfactory Transduction, and suggest that the co-transporter is located basolaterally at the cell body although its presence at the cilia could not be discarded.
Detlev Schild - One of the best experts on this subject based on the ideXlab platform.
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cAMP-independent Olfactory Transduction of amino acids in Xenopus laevis tadpoles.
The Journal of physiology, 2003Co-Authors: Ivan Manzini, Detlev SchildAbstract:Whether odorants are transduced by only one or more than one second messenger has been a long-standing question in Olfactory research. In a previous study we started to address this question mainly by using calcium imaging in the Olfactory bulb. Here, we present direct evidence for our earlier conclusions using the calcium imaging technique in the mucosa slice. The above question can now unambiguously be answered. We show that some Olfactory receptor neurons (ORNs) respond to stimulation with amino acids with an increase of the intracellular calcium concentration [Ca2+]i. In order to see whether or not these responses were mediated by the cAMP Transduction pathway we applied forskolin or the membrane-permeant cAMP analogue pCPT-cAMP to the Olfactory epithelium. The ensemble of ORNs that was activated by amino acids markedly differed from the ensemble of neurons activated by forskolin or pCPT-cAMP. Less than 6 % of the responding ORNs showed a response to both amino acids and the pharmacological agents activating the cAMP Transduction pathway. We conclude that ORNs of Xenopus laevis tadpoles have both cAMP-dependent and cAMP-independent Olfactory Transduction pathways and that most amino acids are transduced in a cAMP-independent way.
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cAMP‐independent Olfactory Transduction of amino acids in Xenopus laevis tadpoles
The Journal of Physiology, 2003Co-Authors: Ivan Manzini, Detlev SchildAbstract:Whether odorants are transduced by only one or more than one second messenger has been a long-standing question in Olfactory research. In a previous study we started to address this question mainly by using calcium imaging in the Olfactory bulb. Here, we present direct evidence for our earlier conclusions using the calcium imaging technique in the mucosa slice. The above question can now unambiguously be answered. We show that some Olfactory receptor neurons (ORNs) respond to stimulation with amino acids with an increase of the intracellular calcium concentration [Ca2+]i. In order to see whether or not these responses were mediated by the cAMP Transduction pathway we applied forskolin or the membrane-permeant cAMP analogue pCPT-cAMP to the Olfactory epithelium. The ensemble of ORNs that was activated by amino acids markedly differed from the ensemble of neurons activated by forskolin or pCPT-cAMP. Less than 6 % of the responding ORNs showed a response to both amino acids and the pharmacological agents activating the cAMP Transduction pathway. We conclude that ORNs of Xenopus laevis tadpoles have both cAMP-dependent and cAMP-independent Olfactory Transduction pathways and that most amino acids are transduced in a cAMP-independent way.
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Second messenger signaling in Olfactory Transduction
Journal of neurobiology, 1996Co-Authors: Diego Restrepo, John H. Teeter, Detlev SchildAbstract:Olfactory receptor neurons respond to odorants with G-protein mediated increases in the concentration of cyclic adenosine 3′,5′-monophosphate (cAMP) and/or inositol 1,4,5-triphosphate (InsP3). These two second messengers directly regulate opening of cAMP- and InsP3-regulated conductances localized to the apical Transduction compartments of the cell (cilia and Olfactory knob). In the presence of physiological concentrations of extracellular Ca2+, these second messenger regulated conductances mediate influx of Ca2+ into the Olfactory neuron resulting in large, localized increases in intracellular Ca2+ ([Ca2+]i). A significant advance in our understanding of the molecular mechanisms of olfaction is the recent realization that this increase in [Ca2+]i plays an important role as a “third messenger” in Olfactory Transduction. Second messenger dependent increases in [Ca2+]i cause opening of ciliary Ca2+-activated Cl−, cation and/or K+ channels that can carry a large percentage of the generator current, thus amplifying the signal substantially. As a result of this sequence of events, the generator potential in Olfactory neurons can be depolarizing, leading to excitation of the neuron, or hyperpolarizing, leading to suppression of basal action potential firing rate. This dual effect of odorants on Olfactory neurons may play an important role in quality coding and in the ability to detect low concentrations of odorants, particularly in complex mixtures. © 1996 John Wiley & Sons, Inc.
Yuriy V. Bobkov - One of the best experts on this subject based on the ideXlab platform.
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Inhibitory signaling in mammalian Olfactory Transduction potentially mediated by Gαo
Molecular and cellular neurosciences, 2020Co-Authors: Elizabeth A. Corey, Kirill Ukhanov, Yuriy V. Bobkov, Jeremy C. Mcintyre, Jeffrey R. Martens, Barry W. AcheAbstract:Olfactory GPCRs (ORs) in mammalian Olfactory receptor neurons (ORNs) mediate excitation through the Gαs family member Gαolf. Here we tentatively associate a second G protein, Gαo, with inhibitory signaling in mammalian Olfactory Transduction by first showing that odor evoked phosphoinositide 3-kinase (PI3K)-dependent inhibition of signal Transduction is absent in the native ORNs of mice carrying a conditional OMP-Cre based knockout of Gαo. We then identify an OR from native rat ORNs that are activated by octanol through cyclic nucleotide signaling and inhibited by citral in a PI3K-dependent manner. We show that the OR activates cyclic nucleotide signaling and PI3K signaling in a manner that reflects its functionality in native ORNs. Our findings lay the groundwork to explore the interesting possibility that ORs can interact with two different G proteins in a functionally identified, ligand-dependent manner to mediate opponent signaling in mature mammalian ORNs.
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The Na+/Ca2+ exchanger inhibitor, KB-R7943, blocks a nonselective cation channel implicated in chemosensory Transduction.
Journal of neurophysiology, 2008Co-Authors: Adeline Pezier, Yuriy V. Bobkov, Barry W. AcheAbstract:The mechanism(s) of Olfactory Transduction in invertebrates remains to be fully understood. In lobster Olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presump...
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Calcium sensitivity of a sodium-activated nonselective cation channel in lobster Olfactory receptor neurons.
Journal of neurophysiology, 2003Co-Authors: Yuriy V. Bobkov, Barry W. AcheAbstract:We report that a Na+-activated nonselective cation channel described previously in lobster Olfactory neurons, in which phosphoinositide signaling mediates Olfactory Transduction, can also be activated by Ca2+. Ca2+ activates the channel in the presence of Na+, increasing the open probability of the channel with a K1/2 of 490 nM and a Hill coefficient of 1.3. Ca2+ also increases the sensitivity of the channel to Na+. In some cells, the same channel is Ca2+ insensitive in a cell-specific manner. The nonspecific activator of protein phosphatases, protamine, applied to the intracellular face of patches containing the channel irreversibly eliminates the sensitivity to Ca2+. This effect can be blocked by okadaic acid, a nonspecific blocker of protein phosphatases, and restored by the catalytic subunit of protein kinase A in the presence of MgATP. The Ca2+-sensitive form of the channel is predominantly expressed in the Transduction zone of the cells in situ. These findings imply that the Ca2+ sensitivity of the channel, and possibly its regulation by phosphorylation, play a role in Olfactory Transduction and help tie activation of the channel to the canonical phosphoinositide turnover pathway.
