RESUMO
CRF and urocortin, administrated systemically, exert peripheral biological actions which may be mediated by brain pathways. We identified brain neuronal activation induced by intravenous (i.v.) injection of CRF and urocortin in conscious rats by monitoring Fos expression 60 min later. Both peptides (850 pmol/kg, i.v.) increased the number of Fos immunoreactive cells in the paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala, nucleus tractus solitarius and area postrema compared with vehicle injection. Urocortin induced a 4-fold increase in the number of Fos-positive cells in the supraoptic nucleus and a 3.4-fold increase in the lateral magnocellular part of the paraventricular nucleus compared with CRF. Urocortin also elicited Fos expression in the accessory hypothalamic neurosecretory nuclei, ependyma lining the ventricles and choroid plexus which was not observed after CRF. The intensity and pattern of the Fos response were dose-related (85, 255 and 850 pmol/kg, i.v.) and urocortin was more potent than CRF. Neither CRF nor urocortin induced Fos expression in the lateral septal nucleus, Edinger-Westphal nucleus, dorsal raphe nucleus, locus coeruleus, or hypoglossal nucleus. These results show that urocortin, and less potently CRF, injected into the circulation at picomolar doses activate selective brain nuclei involved in the modulation of autonomic/endocrine function; in addition, urocortin induces a distinct activation of hypothalamic neuroendocrine neurons.
Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Hipotálamo/metabolismo , Sistemas Neurossecretores/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Tonsila do Cerebelo/química , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Anticorpos , Plexo Corióideo/química , Plexo Corióideo/efeitos dos fármacos , Plexo Corióideo/metabolismo , Epêndima/química , Epêndima/efeitos dos fármacos , Epêndima/metabolismo , Nervo Hipoglosso/química , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/metabolismo , Região Hipotalâmica Lateral/química , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Imuno-Histoquímica , Injeções Intravenosas , Locus Cerúleo/química , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Mesencéfalo/química , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Sistemas Neurossecretores/química , Sistemas Neurossecretores/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/química , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Proto-Oncogênicas c-fos/análise , Proteínas Proto-Oncogênicas c-fos/imunologia , Núcleos da Rafe/química , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/química , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Supraóptico/química , Núcleo Supraóptico/efeitos dos fármacos , Núcleo Supraóptico/metabolismo , Urocortinas , Nervo Vago/química , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
Members of the Kir2 subfamily of inwardly rectifying K+ channels characterized by their strong current rectification are widely expressed both in the periphery and in the CNS in mammals. We have cloned from rat brain a fourth subfamily member, designated Kir2.4 (IRK4), which shares 53-63% similarity to Kir2.1, Kir2.2, or Kir2.3 on the amino acid level. In situ hybridization analysis identifies Kir2.4 as the most restricted of all Kir subunits in the brain. Kir2. 4 transcripts are expressed predominantly in motoneurons of cranial nerve motor nuclei within the general somatic and special visceral motor cell column and thus are uniquely related to a functional system. Heterologous expression of Kir2.4 in Xenopus oocytes and mammalian cells gives rise to low-conductance channels (15 pS), with an affinity to the channel blockers Ba2+ (Ki = 390 microM) and Cs+ (Ki = 8.06 mM) 30-50-fold lower than in other Kir channels. Low Ba2+ sensitivity allows dissection of Kir2.4 currents from other Kir conductances in hypoglossal motoneurons (HMs) in rat brainstem slices. The finding that Ba2+-mediated block of Kir2.4 in HMs evokes tonic activity and increases the frequency of induced spike discharge indicates that Kir2.4 channels are of major importance in controlling excitability of motoneurons in situ.