Abstract
Conventional soluble guanylyl cyclases are heterodimeric enzymes that synthesize cGMP and are activated by nitric oxide. Recently, a separate class of soluble guanylyl cyclases has been identified that are only slightly activated by or are insensitive to nitric oxide. These atypical guanylyl cyclases include the vertebrate beta2 subunit and examples from the invertebrates Manduca sexta, Caenorhabditis elegans, and Drosophila melanogaster. A member of this family, GCY-35 in C. elegans, was recently shown to be required for a behavioral response to low oxygen levels and may be directly regulated by oxygen (Gray, J. M., Karow, D. S., Lu, H., Chang, A. J., Chang, J. S., Ellis, R. E., Marletta, M. A., and Bargmann, C. I. (2004) Nature 430, 317-322). Drosophila contains three genes that code for atypical soluble guanylyl cyclases: Gyc-88E, Gyc-89Da, and Gyc-89Db. COS-7 cells co-transfected with Gyc-88E and Gyc-89Da or Gyc-89Db accumulate low levels of cGMP under normal atmospheric oxygen concentrations and are potently activated under anoxic conditions. The increase in activity is graded over oxygen concentrations of 0-21%, can be detected within 1 min of exposure to anoxic conditions and is blocked by the soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Gyc-88E and Gyc-89Db are co-expressed in a subset of sensory neurons where they would be ideally situated to act as oxygen sensors. This is the first demonstration of a soluble guanylyl cyclase that is activated in response to changing oxygen concentrations.
Highlights
Conventional soluble guanylyl cyclases are heterodimeric enzymes that synthesize cGMP and are activated by nitric oxide
In this report we show that the Drosophila atypical soluble guanylyl cyclase subunits are activated in the absence of oxygen and could act as oxygen sensors, alerting the animals to hypoxic environments
Plasmids containing the open reading frames of the Drosophila soluble guanylyl cyclase subunits were transiently transfected into COS-7 cells in 12-well tissue culture plates as described previously (5). 72 h after transfection, the culture medium was removed from the cells and replaced with physiological saline that had been saturated with a mixture of oxygen and nitrogen
Summary
Conventional soluble guanylyl cyclases are heterodimeric enzymes that synthesize cGMP and are activated by nitric oxide. A separate class of soluble guanylyl cyclases has been identified that are only slightly activated by or are insensitive to nitric oxide. These atypical guanylyl cyclases include the vertebrate 2 subunit and examples from the invertebrates Manduca sexta, Caenorhabditis elegans, and Drosophila melanogaster. Gyc-88E and Gyc-89Db are co-expressed in a subset of sensory neurons where they would be ideally situated to act as oxygen sensors This is the first demonstration of a soluble guanylyl cyclase that is activated in response to changing oxygen concentrations. In this report we show that the Drosophila atypical soluble guanylyl cyclase subunits are activated in the absence of oxygen and could act as oxygen sensors, alerting the animals to hypoxic environments
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