RESUMEN
Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement.
Asunto(s)
Hiperalgesia/metabolismo , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Conducta Animal/efectos de los fármacos , Bradiquinina/efectos adversos , Células CHO , Señalización del Calcio/efectos de los fármacos , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Hiperalgesia/genética , Hiperalgesia/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oocitos , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Canal Catiónico TRPA1 , Transfección/métodos , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/deficiencia , Canales de Potencial de Receptor Transitorio/genética , XenopusRESUMEN
In mammals, a small population of intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a key role in the regulation of nonvisual photic responses, such as behavioral responses to light, pineal melatonin synthesis, pupillary light reflex, and sleep latency. These ipRGCs also express melanopsin (Opn4), a putative opsin-family photopigment that has been shown to play a role in mediating these nonvisual photic responses. Melanopsin is required for the function of this inner retinal pathway, but its precise role in generating photic responses has not yet been determined. We found that expression of melanopsin in Xenopus oocytes results in light-dependent activation of membrane currents through the Galpha(q)/Galpha(11) G protein pathway, with an action spectrum closely matching that of melanopsin-expressing ipRGCs and of behavioral responses to light in mice lacking rods and cones. When coexpressed with arrestins, melanopsin could use all-trans-retinaldehyde as a chromophore, which suggests that it may function as a bireactive opsin. We also found that melanopsin could activate the cation channel TRPC3, a mammalian homolog of the Drosophila phototransduction channels TRP and TRPL. Melanopsin therefore signals more like an invertebrate opsin than like a classical vertebrate rod-and-cone opsin.
Asunto(s)
Fototransducción , Luz , Opsinas de Bastones/fisiología , Transducción de Señal , Animales , Arrestinas/genética , Arrestinas/metabolismo , Calcio/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Proteínas de Unión al GTP/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , Isoenzimas/metabolismo , Ratones , Oocitos/metabolismo , Técnicas de Placa-Clamp , Fosfolipasa C beta , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Células Ganglionares de la Retina/metabolismo , Retinaldehído/metabolismo , Retinaldehído/farmacología , Opsinas de Bastones/genética , Canales Catiónicos TRPC , Fosfolipasas de Tipo C/metabolismo , Xenopus , beta-ArrestinasAsunto(s)
Regulación de la Temperatura Corporal , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Canales Iónicos/metabolismo , Animales , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Drosophila/química , Canales Iónicos/química , Ratones , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Canal Catiónico TRPA1 , Temperatura , Canales de Potencial de Receptor TransitorioRESUMEN
We analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored.A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders.
Asunto(s)
Genes/fisiología , Fenómenos Fisiológicos del Sistema Nervioso , Sistema Nervioso/química , Sistema Nervioso/metabolismo , Transcripción Genética/genética , Adenina/metabolismo , Secuencia de Aminoácidos , Animales , Química Encefálica/genética , Calcio/fisiología , Canales de Calcio/genética , Canales de Calcio/fisiología , Canales de Cloruro/genética , Canales de Cloruro/fisiología , Citosina/metabolismo , Bases de Datos Genéticas , Proteínas de Unión al GTP/genética , Biblioteca de Genes , Genes/genética , Guanina/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Enfermedades Neurodegenerativas/genética , Neuronas/química , Neuronas/metabolismo , Neuronas/fisiología , Neuropéptidos/genética , Filogenia , Receptores de Superficie Celular/genética , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Mammals detect temperature with specialized neurons in the peripheral nervous system. Four TRPV-class channels have been implicated in sensing heat, and one TRPM-class channel in sensing cold. The combined range of temperatures that activate these channels covers a majority of the relevant physiological spectrum sensed by most mammals, with a significant gap in the noxious cold range. Here, we describe the characterization of ANKTM1, a cold-activated channel with a lower activation temperature compared to the cold and menthol receptor, TRPM8. ANKTM1 is a distant family member of TRP channels with very little amino acid similarity to TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with TRPV1/VR1 (the capsaicin/heat receptor) but not TRPM8. Consistent with the expression of ANKTM1, we identify noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.