Glutamate-induced calcium signals stimulate CO production in piglet astrocytes

Xi Q, Tcheranova D, Basuroy S, Parfenova H, Jaggar JH, Leffler CW. Glutamate-induced calcium signals stimulate CO production in piglet astrocytes. Am J Physiol Heart Circ Physiol 301: H428-H433, 2011. First published May 13, 2011; doi:10.1152/ajpheart. 01277.2010.Glutamate-stimulated, astrocyte-derived carbon monoxide (CO) causes cerebral arteriole dilation by activating smooth muscle cell large-conductance Ca2+-activated K+ channels. Here, we examined the hypothesis that glutamate activates heme oxygenase (HO)-2 and CO production via the intracellular Ca2+ concentration ([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, and 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+- and calmodulin-dependent HO-2 activation, and CO production.