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1.
Cell ; 173(3): 762-775.e16, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29677517

RESUMEN

Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.


Asunto(s)
Mecanotransducción Celular , Interferencia de ARN , Receptores Acoplados a Proteínas G/fisiología , Animales , Materiales Biocompatibles , Calcio/metabolismo , Línea Celular Tumoral , Células Endoteliales/fisiología , Endotelio Vascular/citología , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración de Iones de Hidrógeno , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/genética , Resistencia al Corte , Estrés Mecánico , Resistencia Vascular
2.
Nature ; 541(7636): 176-181, 2017 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-28002412

RESUMEN

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.


Asunto(s)
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 Pulmonar
3.
Nature ; 516(7529): 121-5, 2014 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-25471886

RESUMEN

The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.


Asunto(s)
Canales Iónicos/metabolismo , Mecanotransducción Celular/fisiología , Piel/inervación , Tacto/fisiología , Animales , Canales Iónicos/genética , Mecanorreceptores/metabolismo , Mecanotransducción Celular/genética , Células de Merkel/fisiología , Ratones , Ratones Noqueados , Células Receptoras Sensoriales/fisiología , Tacto/genética
4.
Sci Transl Med ; 10(462)2018 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-30305457

RESUMEN

The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of Piezo2-expressing sensory neurons induced nociception in mice. Mice lacking Piezo2 in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Aδ-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin-induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury-induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia.


Asunto(s)
Hiperalgesia/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular , Dolor/metabolismo , Potenciales de Acción , Animales , Conducta Animal , Capsaicina , Hiperalgesia/complicaciones , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Canales Iónicos/deficiencia , Ratones Noqueados , Neuronas/metabolismo , Nocicepción , Nociceptores/metabolismo , Dolor/complicaciones , Dolor/patología , Dolor/fisiopatología
5.
Nat Neurosci ; 18(12): 1756-62, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26551544

RESUMEN

Proprioception, the perception of body and limb position, is mediated by proprioceptors, specialized mechanosensory neurons that convey information about the stretch and tension experienced by muscles, tendons, skin and joints. In mammals, the molecular identity of the stretch-sensitive channel that mediates proprioception is unknown. We found that the mechanically activated nonselective cation channel Piezo2 was expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice. Two independent mouse lines that lack Piezo2 in proprioceptive neurons showed severely uncoordinated body movements and abnormal limb positions. Moreover, the mechanosensitivity of parvalbumin-expressing neurons that predominantly mark proprioceptors was dependent on Piezo2 expression in vitro, and the stretch-induced firing of proprioceptors in muscle-nerve recordings was markedly reduced in Piezo2-deficient mice. Together, our results indicate that Piezo2 is the major mechanotransducer of mammalian proprioceptors.


Asunto(s)
Canales Iónicos/deficiencia , Canales Iónicos/genética , Mecanotransducción Celular/fisiología , Propiocepción/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Células Cultivadas , Femenino , Ganglios Espinales/fisiología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Trastornos del Movimiento/genética , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología
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