Effect of prolonged O2 deprivation on Na+ channels: differential regulation in adult versus fetal rat brain.

Neuronal Na+ channels are functionally inhibited in the adult in response to acute O2 deprivation. Since prolonged hypoxia may not only affect channel function, but also its expression, we hypothesized that long-term hypoxia alters Na+ channel density. This alteration may depend on age, because we have found major differences in neuronal responses to hypoxia between the immature and adult. In the present work, we used northern blots, slot blots, saxitoxin binding and autoradiography to ask whether: (i) prolonged hypoxia alters Na+ channel messenger RNA and protein levels in the brain; (ii) there is a difference between the adult and prenatal brains regarding Na+ channel expression with hypoxic exposure; and (iii) regional differences in Na+ channel expression occur in hypoxia-exposed brains. Our results show the following. (1) Na+ channel messenger RNA and saxitoxin binding density decreased after prolonged hypoxia in adult brain homogenates; this is in sharp contrast to the changes observed in fetal brains, which tended to increase Na+ channel messenger RNA and protein after hypoxia. (2) Changes in saxitoxin binding density are related to alterations in the number of saxitoxin binding sites and not to binding affinity, since there was no major change in Kd values between the hypoxia and naive groups. (3) The hypoxia-induced Na+ channel expression was heterogeneous, with major differences between rostral regions (e.g., the cortex) and caudal regions (e.g., the medulla and pons). We speculate that down-regulation of Na+ channels during long-term hypoxia in mature brains is an adaptive cellular response, aimed at minimizing the mismatch between energy supply and demand, since maintenance of Na+ gradients is a major energy-requiring process. However, the prenatal brain does not depend on this adaptive mechanism in response to hypoxic stress.