RESUMO
Hypoxia is damaging in neurons, but it can also produce beneficial effects by consolidating the activity of neural networks such as facilitation of respiratory activity [T.L. Baker-Herman, D.D. Fuller, R.W. Bavis, A.G. Zabka, F.J. Golder, N.J. Doperalski, R.A. Johnson, J.J. Watters, G.S. Mitchell, Nature Neuroscience 7 (2004) 48-55; J.L. Feldman, G.S. Mitchell, E.E. Nattie, Ann. Rev. Neurosci. 26 (2003) 239-266; D.M. Blitz, J.M. Ramirez, J. Neurophysiol. 87 (2002) 2964-2971]. The underlying mechanisms are unknown, and we hypothesized they may be similar to ischemic preconditioning in the heart, involving mitochondrial K(ATP) (mK(ATP)) channels. By measuring the mitochondrial potential (Psi(m)) and Ca2+ ([Ca2+]m) in neurons of pre-Botzinger complex (pBC), we examined the functional expression of mK(ATP) channels in the respiratory network. The opener of mK(ATP) channels diazoxide decreased Psi(m) and [Ca2+]m both in pBC neurons and in isolated immobilized mitochondria. 5-Hydroxydecanoate (5-HD), the blocker of mK(ATP) channels, increased both Psi(m) and [Ca2+]m. Phorbol 12-myristate-13-acetate (PMA) mimicked the effects of diazoxide. Protein kinase C (PKC) was stimulated during hypoxia that occurred mostly at the mitochondria. Brief hypoxia induced facilitation of the respiratory activity, which was prevented after blockade of mK(ATP) channels with 5-HD and PKC with staurosporine. Diazoxide potentiated the motor output and subsequent application of hypoxia was ineffective. We propose that a PKC-induced stimulation of K(ATP) channels in the mitochondria of respiratory neurons is responsible for the hypoxic facilitation of rhythmic activity.
