Fluorocitrate-mediated depolarization of astrocytes in the retrotrapezoid nucleus stimulates breathing

Autor(es)

Sobrinho, Cleyton R. ; Goncalves, Christopher M. ; Takakura, Ana C. ; Mulkey, Daniel K. ; Moreira, Thiago S.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Neurophysiology; v. 118, n. 3, p. 1690-1697, SEP 2017.
• Citações Web of Science: 6

Resumo

Evidence indicates that CO2 /H+-evoked ATP released from retrotrapezoid nucleus (RTN) astrocytes modulates the activity of CO2-sensitive neurons. RTN astrocytes also sense H+ by inhibition of Kir4.1 channels; however, the relevance of this pH-sensitive current remains unclear since ATP release appears to involve CO2-dependent gating of connexin 26 hemichannels. Considering that depolarization mediated by H+ inhibition of Kir4.1 channels is expected to increase sodium bicarbonate cotransporter (NBC) conductance and favor Ca2+ influx via the sodium calcium exchanger (NCX), we hypothesize that depolarization in the presence of CO2 is sufficient to facilitate ATP release and enhance respiratory output. Here, we confirmed that acute exposure to fluorocitrate (FCt) reversibly depolarizes RTN astrocytes and increased activity of RTN neurons by a purinergic-dependent mechanism. We then made unilateral injections of FCt into the RTN or two other putative chemoreceptor regions (NTS and medullary raphe) to depolarize astrocytes under control conditions and during P2-recepetor blockade while measuring cardiorespiratory activities in urethane-anesthetized, vagotomized, artificially ventilated male Wistar rats. Unilateral injection of FCt into the RTN increased phrenic (PNA) amplitude and frequency without changes in arterial pressure. Unilateral injection of pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS, a P2-receptor antagonist) into the RTN dampened both PNA amplitude and frequency responses to FCt. Injection of MRS2179 (P2Y1-receptor antagonist) into the RTN did not affect the FCt-induced respiratory responses. Fluorocitrate had no effect on breathing when injected into the NTS or raphe. These results suggest that depolarization can facilitate purinergic enhancement of respiratory drive from the RTN. NEW \& NOTEWORTHY Astrocytes in the retrotrapezoid nucleus (RTN) are known to function as respiratory chemoreceptors; however, it is not clear whether changes in voltage contribute to astrocyte chemoreception. We showed that depolarization of RTN astrocytes at constant CO2 levels is sufficient to modulate RTN chemoreception by a purinergic-dependent mechanism. These results support the possibility that astrocyte depolarization can facilitate purinergic enhancement of respiratory drive from the RTN. (AU)

• Processo FAPESP: 14/22406-1 - Alterações respiratórias anatomofuncionais observadas em um modelo experimental da Doença de Parkinson
• Beneficiário: Ana Carolina Takakura Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/13462-7 - Interação entre astrócitos e neurônios do núcleo retrotrapezóide nas respostas respiratórias promovidas pela ativação do quimiorreflexo central
• Beneficiário: Cleyton Roberto Sobrinho
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/23376-1 - Núcleo retrotrapezóide, quimiossensibilidade central e automaticidade respiratória
• Beneficiário: Thiago dos Santos Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/12827-2 - Sinalização colinérgica e ventilação: ação modulatória do núcleo tegmental peduncúlo-pontino sobre o núcleo retrotrapezóide
• Beneficiário: Cleyton Roberto Sobrinho
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/22069-0 - Melhora nos mecanismos de regulação do fluxo sanguíneo encefálico em animais espontaneamente hipertensos: participação do exercício físico
• Beneficiário: Thiago dos Santos Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular