Soluble guanylate cyclases (sGCs) are gas-binding proteins that control diverse physiological processes such as vasodilation, platelet aggregation, and synaptic plasticity. In the nematodeCaenorhabditis elegans, a complex of sGCs, GCY-35 and GCY-36, functions in oxygen (O₂) sensing. Previous studies suggested that the neuroglobin GLB-5 genetically interacts with GCY-35, and that the inhibitory effect of GLB-5 on GCY-35 function is necessary for fast recovery from prolonged hypoxia. In this study, we identified mutations ingcy-35andgcy-36that impact fast recovery and other phenotypes associated with GLB-5, without undermining sGC activity. These mutations,heb1andheb3, change conserved amino acid residues in the regulatory H-NOX domains of GCY-35 and GCY-36, respectively, and appear to suppress GLB-5 activity by different mechanisms. Moreover, we observed that short exposure to 35% O₂desensitized the neurons responsible for ambient O₂sensing and that this phenomenon does not occur inheb1animals. These observations may implicate sGCs in neuronal desensitization mechanisms far beyond the specific case of O₂sensing in nematodes. The conservation of functionally important regions of sGCs is supported by examining site-directed mutants of GCY-35, which suggested that similar regions in the H-NOX domains of O₂and NO-sensing sGCs are important for heme/gas interactions. Overall, our studies provide novel insights into sGC activity and regulation, and implicate similar structural determinants in the control of both O₂and NO sensors.SIGNIFICANCE STATEMENTSoluble guanylate cyclases (sGCs) control essential and diverse physiological processes, including memory processing. We usedCaenorhabditis elegansto explore how a neuroglobin inhibits a complex of oxygen-sensing sGCs, identifying sGC mutants that resist inhibition. Resistance appears to arise by two different mechanisms: increased basal sGC activity or disruption of an interaction with neuroglobin. Our findings demonstrate that the inhibition of sGCs by neuroglobin is essential for rapid adaptation to either low or high oxygen levels, and that similar structural regions are key for regulating both oxygen and nitric oxide sensors. Based on our structural and functional analyses, we present the hypothesis that neuroglobin-sGC interactions may be generally important for adaptation processes, including those in organisms with more complex neurological functions.