RESUMEN
Task2 K(+) channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including the retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost in mice bearing a Phox2b mutation that causes the human congenital central hypoventilation syndrome. In plethysmography, Task2(-/-) mice showed disturbed chemosensory function with hypersensitivity to low CO(2) concentrations, leading to hyperventilation. Task2 probably is needed to stabilize the membrane potential of chemoreceptive cells. In addition, Task2(-/-) mice lost the long-term hypoxia-induced respiratory decrease whereas the acute carotid-body-mediated increase was maintained. The lack of anoxia-induced respiratory depression in the isolated brainstem-spinal cord preparation suggested a central origin of the phenotype. Task2 activation by reactive oxygen species generated during hypoxia could silence RTN neurons, thus contributing to respiratory depression. These data identify Task2 as a determinant of central O(2) chemoreception and demonstrate that this phenomenon is due to the activity of a small number of neurons located at the ventral medullary surface.
Asunto(s)
Dióxido de Carbono/fisiología , Oxígeno/fisiología , Canales de Potasio de Dominio Poro en Tándem/fisiología , Centro Respiratorio/fisiología , Animales , Animales Recién Nacidos , Tronco Encefálico/patología , Tronco Encefálico/fisiología , Tronco Encefálico/fisiopatología , Células Quimiorreceptoras/patología , Células Quimiorreceptoras/fisiología , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/fisiología , Humanos , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Pletismografía Total , Canales de Potasio de Dominio Poro en Tándem/deficiencia , Canales de Potasio de Dominio Poro en Tándem/genética , Embarazo , Fenómenos Fisiológicos Respiratorios , Apnea Central del Sueño/etiología , Apnea Central del Sueño/genética , Apnea Central del Sueño/fisiopatología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/fisiologíaRESUMEN
The nucleoside adenosine has been implicated in the regulation of respiration, especially during hypoxia in the newborn. In this study the role of adenosine A1 receptors for the control of respiration was investigated in vivo. To this end, respiration of unrestrained adult and neonatal adenosine A1 receptor knockout mice (A1R(-/-)) was measured in a plethysmographic device. Under control conditions (21% O2) and mild hypoxia (12-15% O2) no difference of respiratory parameters was observed between adult wildtype (A1R(+/+)) and A1R(-/-) mice. Under more severe hypoxia (6-10% O2) A1R(+/+) mice showed, after a transient increase of respiration, a decrease of respiration frequency (fR) and tidal volume (VT) leading to a decrease of minute volume (MV). This depression of respiration during severe hypoxia was absent in A1R(-/-) mice which displayed a stimulated respiration as indicated by the enhancement of MV by some 50-60%. During hypercapnia-hyperoxia (3-10% CO2/97-90 % O2), no obvious differences in respiration of A1R(-/-) and A1R(+/+) was observed. In neonatal mice, the respiratory response to hypoxia was surprisingly similar in both genotypes. However, neonatal A1R(-/-) mice appeared to have more frequently periods of apnea during hypoxia and in the post-hypoxic control period. In conclusion, these data indicate that the adenosine A1 receptor is an important molecular component mediating hypoxic depression in adult mice and it appears to stabilize respiration of neonatal mice.