RESUMEN
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
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Dermatitis Atópica , Inmunidad Innata , Pulmón , Células Receptoras Sensoriales , Animales , Humanos , Ratones , Citocinas , Dermatitis Atópica/inmunología , Inflamación , Pulmón/inmunología , Linfocitos , Células Receptoras Sensoriales/enzimologíaRESUMEN
Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.
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Vías Nerviosas , Neuronas/metabolismo , Células Receptoras Sensoriales/metabolismo , Nervio Vago/metabolismo , Animales , Ganglios/metabolismo , Motilidad Gastrointestinal , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Optogenética , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Estómago/inervaciónRESUMEN
Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping revealed that these neurons densely innervate the lung and send long-range projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers, while P2ry1 neurons are largely fast-conducting A fibers that contact pulmonary endocrine cells (neuroepithelial bodies). Optogenetic stimulation of P2ry1 neurons acutely silences respiration, trapping animals in exhalation, while stimulating Npy2r neurons causes rapid, shallow breathing. Activating P2ry1 neurons did not impact heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.
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Respiración , Células Receptoras Sensoriales/fisiología , Nervio Vago/citología , Animales , Tronco Encefálico/fisiología , Pulmón/inervación , Ratones , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriales/citología , Nervio Vago/fisiologíaRESUMEN
Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
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Percepción , Psicofisiología , Nervio Vago , Órgano Vomeronasal , Animales , Encéfalo/metabolismo , Calcio/metabolismo , Mamíferos/metabolismo , Ratones , Células Receptoras Sensoriales/metabolismoRESUMEN
Interoception, the ability to precisely and timely sense internal body signals, is critical for life. The interoceptive system monitors a large variety of mechanical, chemical, hormonal, and pathological cues using specialized organ cells, organ innervating neurons, and brain sensory neurons. It is important for maintaining body homeostasis, providing motivational drives, and regulating autonomic, cognitive, and behavioral functions. However, compared to external sensory systems, our knowledge about how diverse body signals are coded at a system level is quite limited. In this review, we focus on the unique features of interoceptive signals and the organization of the interoceptive system, with the goal of better understanding the coding logic of interoception.
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Interocepción , Humanos , Interocepción/fisiología , Encéfalo/fisiología , Señales (Psicología) , LógicaRESUMEN
The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit-derived and heart-brain circuit-derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.
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Enfermedades Cardiovasculares , Sistema Cardiovascular , Humanos , Corazón , Neuronas/fisiología , EncéfaloRESUMEN
Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering-Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults.
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Apnea/fisiopatología , Canales Iónicos/metabolismo , Pulmón/fisiología , Pulmón/fisiopatología , Mecanotransducción Celular/fisiología , Reflejo/fisiología , Animales , Animales Recién Nacidos , Apnea/genética , Muerte , Femenino , Canales Iónicos/deficiencia , Canales Iónicos/genética , Masculino , Mecanotransducción Celular/genética , Ratones , Ganglio Nudoso/metabolismo , Reflejo/genética , Respiración , Células Receptoras Sensoriales/metabolismo , Volumen de Ventilación PulmonarRESUMEN
Sour taste is detected by a subset of taste cells on the tongue and palate epithelium that respond to acids with trains of action potentials. Entry of protons through a Zn(2+)-sensitive proton conductance that is specific to sour taste cells has been shown to be the initial event in sour taste transduction. Whether this conductance acts in concert with other channels sensitive to changes in intracellular pH, however, is not known. Here, we show that intracellular acidification generates excitatory responses in sour taste cells, which can be attributed to block of a resting K(+) current. We identify KIR2.1 as the acid-sensitive K(+) channel in sour taste cells using pharmacological and RNA expression profiling and confirm its contribution to sour taste with tissue-specific knockout of the Kcnj2 gene. Surprisingly, acid sensitivity is not conferred on sour taste cells by the specific expression of Kir2.1, but by the relatively small magnitude of the current, which makes the cells exquisitely sensitive to changes in intracellular pH. Consistent with a role of the K(+) current in amplifying the sensory response, entry of protons through the Zn(2+)-sensitive conductance produces a transient block of the KIR2.1 current. The identification in sour taste cells of an acid-sensitive K(+) channel suggests a mechanism for amplification of sour taste and may explain why weak acids that produce intracellular acidification, such as acetic acid, taste more sour than strong acids.
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Canales de Potasio de Rectificación Interna/metabolismo , Protones , Transducción de Señal , Gusto/fisiología , Ácidos/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Canales de Calcio/metabolismo , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Integrasas/metabolismo , Espacio Intracelular/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Ratones Noqueados , Modelos Biológicos , Especificidad de Órganos/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Canales Catiónicos TRPM/metabolismo , Gusto/efectos de los fármacos , Papilas Gustativas/citología , Papilas Gustativas/efectos de los fármacos , Papilas Gustativas/metabolismo , Zinc/farmacologíaRESUMEN
Five tastes have been identified, each of which is transduced by a separate set of taste cells. Of these sour, which is associated with acid stimuli, is the least understood. Genetic ablation experiments have established that sour is detected by a subset of taste cells that express the TRP channel PKD2L1 and its partner PKD1L3, however the mechanisms by which this subset of cells detects acids remain unclear. Previous efforts to understand sour taste transduction have been hindered because sour responsive cells represent only a small fraction of cells in a taste bud, and numerous ion channels with no role in sour sensing are sensitive to acidic pH. To identify acid-sensitive conductances unique to sour cells, we created genetically modified mice in which sour cells were marked by expression of YFP under the control of the PKD2L1 promoter. To measure responses to sour stimuli we developed a method in which suction electrode recording is combined with UV photolysis of NPE-caged proton. Using these methods, we report that responses to sour stimuli are not mediated by Na(+) permeable channels as previously thought, but instead are mediated by a proton conductance specific to PKD2L1-expressing taste cells. This conductance is sufficient to drive action potential firing in response to acid stimuli, is enriched in the apical membrane of PKD2L1-expressing taste cells and is not affected by targeted deletion of the PKD1L3 gene. We conclude that, during sour transduction, protons enter through an apical proton conductance to directly depolarize the taste cell membrane.
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Canales de Calcio/metabolismo , Potenciales de la Membrana/fisiología , Protones , Receptores de Superficie Celular/metabolismo , Canales Catiónicos TRPP/metabolismo , Papilas Gustativas/metabolismo , Gusto/fisiología , Animales , Canales de Calcio/genética , Concentración de Iones de Hidrógeno , Ratones , Ratones Transgénicos , Receptores de Superficie Celular/genética , Canales Catiónicos TRPP/genética , Papilas Gustativas/citologíaRESUMEN
The organ-intrinsic nervous system is a major interface between visceral organs and the brain, mediating important sensory and regulatory functions in the body-brain axis and serving as critical local processors for organ homeostasis. Molecularly, anatomically, and functionally, organ-intrinsic neurons are highly specialized for their host organs. However, the underlying mechanism that drives this specialization is largely unknown. Here, we describe the differential strategies utilized to achieve organ-specific organization between the enteric nervous system (ENS) 1 and the intrinsic cardiac nervous system (ICNS) 2 , a neuronal network essential for heart performance but poorly characterized. Integrating high-resolution whole-embryo imaging, single-cell genomics, spatial transcriptomics, proteomics, and bioinformatics, we uncover that unlike the ENS which is highly mobile and colonizes the entire gastrointestinal (GI) tract, the ICNS uses a rich set of extracellular matrix (ECM) genes that match with surrounding heart cells and an intermediate dedicated neuronal progenitor state to stabilize itself for a 'beads-on-the-necklace' organization on heart atria. While ICNS- and ENS-precursors are genetically similar, their differentiation paths are influenced by their host-organs, leading to distinct mature neuron types. Co-culturing ENS-precursors with heart cells shifts their identity towards the ICNS and induces the expression of heart-matching ECM genes. Our cross-organ study thus reveals fundamental principles for the maturation and specialization of organ-intrinsic neurons.
RESUMEN
Sleep scoring is a tedious, time-consuming process that presents a huge challenge in clinics. Leveraging the state-of-the-art U-net architecture, Zhang et al. developed a deep learning algorithm to simultaneously annotate basic and pathologic sleep stages. This model can analyze a full-length sleep record in a few seconds with high accuracy.
RESUMEN
The baroreflex is essential for blood pressure homeostasis. In this issue of Neuron, Yao et al.1 uncover a novel role of brainstem barosensitive neurons in promoting non-REM (NREM) sleep, providing a direct link between the cardiovascular system and sleep-wake states.
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Sistema Cardiovascular , SueñoRESUMEN
In humans, high concentrations of CO(2), as found in carbonated beverages, evoke a mixture of sensations that include a stinging or pungent quality. The stinging sensation is thought to originate with the activation of nociceptors, which innervate the respiratory, nasal, and oral epithelia. The molecular basis for this sensation is unknown. Here we show that CO(2) specifically activates a subpopulation of trigeminal neurons that express TRPA1, a mustard oil- and cinnamaldehyde-sensitive channel, and that these responses are dependent on a functional TRPA1 gene. TRPA1 is sufficient to mediate responses to CO(2) as TRPA1 channels expressed in HEK-293 cells, but not TRPV1 channels, were activated by bath-applied CO(2). CO(2) can diffuse into cells and produce intracellular acidification, which could gate TRPA1 channels. Consistent with this mechanism, TRPA1 channels in excised patches were activated in a dose-dependent manner by intracellular protons. We conclude that TRPA1, by sensing intracellular acidification, constitutes an important component of the nociceptive response to CO(2).
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Dióxido de Carbono/fisiología , Nociceptores/fisiología , Células Receptoras Sensoriales/fisiología , Canales de Potencial de Receptor Transitorio/fisiología , Nervio Trigémino/fisiología , Acroleína/análogos & derivados , Acroleína/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Línea Celular , Humanos , Concentración de Iones de Hidrógeno , Líquido Intracelular/efectos de los fármacos , Líquido Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Boca/efectos de los fármacos , Boca/inervación , Nociceptores/efectos de los fármacos , Técnicas de Placa-Clamp/métodos , Ratas , Células Receptoras Sensoriales/efectos de los fármacos , Canal Catiónico TRPA1 , Canales de Potencial de Receptor Transitorio/agonistas , Canales de Potencial de Receptor Transitorio/biosíntesis , Nervio Trigémino/efectos de los fármacosRESUMEN
Our understanding of the gut system has been revolutionized over the past decade, in particular regarding its role in immune control and psychological regulation. The vagus nerve is a crucial link between gut and brain, transmitting diverse gut-derived signals, and has been implicated in many gastrointestinal, neurological, and immunological disorders. Using state-of-the-art technologies including single-cell genomic analysis, real-time neural activity recording, trans-synaptic tracing, and electron microscopy, novel physiological functions of vagal gut afferents have been uncovered, and new gut-to-brain pathways have been revealed. Here, we review the most recent findings on vagal sensory neurons and the gut-brain signaling, focusing on the anatomical basis and the underlying molecular and cellular mechanisms. Such new discoveries explain some of the old puzzling problems and also raise new questions in this exciting and rapidly growing field.
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Microbioma Gastrointestinal , Encéfalo , Células Receptoras Sensoriales , Transducción de Señal , Nervio VagoRESUMEN
The peripheral nervous system (PNS) is highly complicated and heterogenous. Conventional neuromodulatory approaches have revealed numerous essential biological functions of the PNS and provided excellent tools to treat a large variety of human diseases. Yet growing evidence indicated the importance of cell-type-specific neuromodulation in the PNS in not only biological research using animal models but also potential human therapies. Optogenetics is a recently developed neuromodulatory approach combining optics and genetics that can effectively stimulate or silence neuronal activity with high spatial and temporal precision. Here, I review research regarding optogenetic manipulations for cell-type-specific control of the PNS, highlighting the advantages and challenges of current optogenetic tools, and discuss their potential future applications.
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Neuronas/fisiología , Optogenética , Sistema Nervioso Periférico/fisiología , Animales , Animales Modificados Genéticamente , HumanosRESUMEN
While thermosensation from external environment has been extensively studied, physiological responses to temperature changes inside the body and the underlying regulatory mechanisms are less understood. As a critical link between body and brain that relays visceral organ information and regulates numerous physiological functions, the vagus nerve has been proposed to mediate diverse visceral thermal reflexes and indirectly regulate body temperature. However, the precise role of the vagus nerve in body thermal responses or visceral organ-related thermoregulation is still under debate due to extensive contradictory results. This data discrepancy is likely due to the high cell heterogeneity in the vagus nerve, as diverse vagal neuron types mediate numerous and sometimes opposite physiological functions. Here, we will review evidences that support and against the role of the vagus nerve in body thermosensation and thermoregulation and discuss potential future approaches for better understanding of this critical issue.
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Regulación de la Temperatura Corporal/fisiología , Temperatura Corporal/fisiología , Metabolismo Energético/fisiología , Nervio Vago/fisiología , Animales , Humanos , Neuronas/fisiología , Reflejo/fisiologíaRESUMEN
Mechanosensory neurons across physiological systems sense force using diverse terminal morphologies. Arterial baroreceptors are sensory neurons that monitor blood pressure for real-time stabilization of cardiovascular output. Various aortic sensory terminals have been described, but those that sense blood pressure are unclear because of a lack of selective genetic tools. Here, we find that all baroreceptor neurons are marked in Piezo2-ires-Cre mice and then use genetic approaches to visualize the architecture of mechanosensory endings. Cre-guided ablation of vagal and glossopharyngeal PIEZO2 neurons eliminates the baroreceptor reflex and aortic depressor nerve effects on blood pressure and heart rate. Genetic mapping reveals that PIEZO2 neurons form a distinctive mechanosensory structure: macroscopic claws that surround the aortic arch and exude fine end-net endings. Other arterial sensory neurons that form flower-spray terminals are dispensable for baroreception. Together, these findings provide structural insights into how blood pressure is sensed in the aortic vessel wall.
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Sistema Nervioso Autónomo/metabolismo , Presión Sanguínea/fisiología , Interocepción/fisiología , Ganglio Nudoso/metabolismo , Presorreceptores/metabolismo , Animales , Mecanotransducción Celular/fisiología , Ratones , Neuronas/metabolismo , Nervio Vago/metabolismoRESUMEN
Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance.
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Regulación del Apetito/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Ingestión de Energía/fisiología , Metabolismo Energético , Femenino , Masculino , Ratones , Neuronas/metabolismoRESUMEN
Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.
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Depresores del Apetito/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Hipotálamo/efectos de los fármacos , Liraglutida/uso terapéutico , Neuronas/efectos de los fármacos , Obesidad/tratamiento farmacológico , Animales , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/efectos de los fármacos , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Genes Reporteros/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/química , Receptor del Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteínas Fluorescentes Verdes/química , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patología , Masculino , Ratones Noqueados , Ratones Transgénicos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Distribución Aleatoria , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/química , Proteína 2 de Transporte Vesicular de Glutamato/genética , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/química , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo , Pérdida de Peso/efectos de los fármacosRESUMEN
Ion channels form the basis for cellular electrical signaling. Despite the scores of genetically identified ion channels selective for other monatomic ions, only one type of proton-selective ion channel has been found in eukaryotic cells. By comparative transcriptome analysis of mouse taste receptor cells, we identified Otopetrin1 (OTOP1), a protein required for development of gravity-sensing otoconia in the vestibular system, as forming a proton-selective ion channel. We found that murine OTOP1 is enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance. Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology.