Glutamate-stimulated, astrocyte-derived carbon monoxide (CO) causes cerebral arteriole dilation by activating smooth muscle cell large-conductance Ca2+-activated potassium (BKCa) channels. Here, we examined the hypothesis that glutamate activates heme oxygenase (HO)-2 and CO production via the [Ca2+]i/Ca2+-calmodulin signaling pathway in newborn pig astrocytes. The major findings are: 1) Glutamate stimulated Ca2+ transients and increased steady-state [Ca2+]i in cerebral cortical astrocytes in primary culture. 2) In astrocytes permeabilized with ionomycin, elevation of [Ca2+]i concentration-dependently increased CO production. 3) Glutamate did not affect CO production at any [Ca2+]i when the [Ca2+]i was held constant. 4) Thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase blocker, decreased basal CO production and blocked glutamate-induced increases in CO. 5) Calmidazolium, a calmodulin inhibitor, blocked CO production induced by glutamate and by [Ca2+]i elevation. Taken together, our data are consistent with the hypothesis that glutamate elevates [Ca2+]i in astrocytes, leading to Ca2+-calmodulin dependent HO-2 activation, and CO production.
- cerebral circulation
- heme oxygenase
- neurovascular coupling
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology