Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

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