HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity

Autor(es)

Hawkins, Virginia E. ^[1] ; Hawrvluk, Joanna M. ^[1] ; Takakura, Ana C. ^[2] ; Tzingounis, Anastasios V. ^[1] ; Moreira, Thiago S. ^[3] ; Mulkey, Daniel K. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Connecticut, Dept Physiol & Neurobiol, Storrs, CT 06269 - USA

^[2] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Physiol & Biophys, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Neurophysiology; v. 113, n. 4, p. 1195-1205, FEB 15 2015.
• Citações Web of Science: 21

Resumo

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2/H+-dependent drive to breathe and function as an integration center for the respiratory network, including scrotonergic raphe neurons. We recently showed that serotonergic modulation of RTN chemoreceptors involved inhibition of KeNQ channels and activation of an unknown inward current. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are the molecular correlate of the hyperpolarization-activated inward current (I-h) and have a high propensity for modulation by serotonin. To investigate whether HCN channels contribute to basal activity and serotonergic modulation of RTN chemoreceptors, we characterize resting activity and the effects of serotonin on WIN chemoreceptors in vitro and on respiratory activity of anesthetized rats in the presence or absence of blockers of KCNQ (XE991) and/or HCN (2D7288, C-s(+)) channels. We found in vivo that bilateral RTN injections of ZD7288 increased respiratory activity and in vitro HCN channel blockade increased activity of WIN chemoreceptors under control conditions, but- this was blunted by KCNQ channel inhibition. Furthermore, in vivo unilateral RTN injection of XE991 plus ZD7288 eliminated the serotonin response, and in vitro serotonin sensitivity was eliminated by application of XE991 and ZD7288 or SQ22536 (adenylate cyclase blocker). Serotonin-mediated activation of WIN chemoreceptors was blocked by a 5-HT7-receptor Mocker and mimicked by a 5-HT7-receptor agonist. In addition, serotonin caused a depolarizing shift in the voltage-dependent activation of I-h. These results suggest that HCN channels contribute to resting chemoreceptor activity and that serotonin activates RTN chemoreceptors and breathing in part by a 5-HT7 receptor-dependent mechanism and downstream activation of I-h. (AU)

• Processo FAPESP: 10/09776-3 - Mecanismos neurais envolvidos na geração do ritmo expiratório: possível envolvimento do núcleo retrotrapezoide e da região parafacial
• Beneficiário: Ana Carolina Takakura Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 09/54888-7 - Mecanismos neurais envolvidos na quimiorrecepção
• Beneficiário: Eduardo Colombari
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/10573-8 - Mecanismos neurais da superfície ventral do bulbo envolvidos na quimiorrecepção
• Beneficiário: Thiago dos Santos Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular