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PMID:23940325

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Citation

Couto, A, Oda, S, Nikolaev, VO, Soltesz, Z and de Bono, M (2013) In vivo genetic dissection of O2-evoked cGMP dynamics in a Caenorhabditis elegans gas sensor. Proc. Natl. Acad. Sci. U.S.A. 110:E3301-10

Abstract

cGMP signaling is widespread in the nervous system. However, it has proved difficult to visualize and genetically probe endogenously evoked cGMP dynamics in neurons in vivo. Here, we combine cGMP and Ca(2+) biosensors to image and dissect a cGMP signaling network in a Caenorhabditis elegans oxygen-sensing neuron. We show that a rise in O2 can evoke a tonic increase in cGMP that requires an atypical O2-binding soluble guanylate cyclase and that is sustained until oxygen levels fall. Increased cGMP leads to a sustained Ca(2+) response in the neuron that depends on cGMP-gated ion channels. Elevated levels of cGMP and Ca(2+) stimulate competing negative feedback loops that shape cGMP dynamics. Ca(2+)-dependent negative feedback loops, including activation of phosphodiesterase-1 (PDE-1), dampen the rise of cGMP. A different negative feedback loop, mediated by phosphodiesterase-2 (PDE-2) and stimulated by cGMP-dependent kinase (PKG), unexpectedly promotes cGMP accumulation following a rise in O2, apparently by keeping in check gating of cGMP channels and limiting activation of Ca(2+)-dependent negative feedback loops. Simultaneous imaging of Ca(2+) and cGMP suggests that cGMP levels can rise close to cGMP channels while falling elsewhere. O2-evoked cGMP and Ca(2+) responses are highly reproducible when the same neuron in an individual animal is stimulated repeatedly, suggesting that cGMP transduction has high intrinsic reliability. However, responses vary substantially across individuals, despite animals being genetically identical and similarly reared. This variability may reflect stochastic differences in expression of cGMP signaling components. Our work provides in vivo insights into the architecture of neuronal cGMP signaling.

Links

PubMed PMC3761592 Online version:10.1073/pnas.1217428110

Keywords

Animals; Biosensing Techniques; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Calcium/metabolism; Cyclic GMP/metabolism; Enzyme Activation; Gases/analysis; Oxygen/metabolism; Phosphoric Diester Hydrolases/metabolism; Signal Transduction; Synapses/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:A8WI01

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O18696

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:A8WI01

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:A8WI01

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:G5EEE2

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:G5EEE2

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:GCY35

involved_in

GO:0019934: cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:GCY35

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE1

enables

GO:0004115: 3',5'-cyclic-AMP phosphodiesterase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:PDE1

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:PDE1

enables

GO:0047555: 3',5'-cyclic-GMP phosphodiesterase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:PDE1

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:A8WI01

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE1

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE1

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:EGL4

involved_in

GO:1902160: negative regulation of cyclic nucleotide-gated ion channel activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:A8WI01

P

  • occurs_in:(WBbt:0004096)
  • has_input:(UniProtKB:A8WI01)

Seeded From UniProt

complete

CAEEL:EGL4

involved_in

GO:0051343: positive regulation of cyclic-nucleotide phosphodiesterase activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:O18696

P

  • occurs_in:(WBbt:0004096)
  • has_input:(UniProtKB:P30645)

Seeded From UniProt

complete

CAEEL:EGL4

involved_in

GO:0010753: positive regulation of cGMP-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:A8WI01

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:EGL4

involved_in

GO:0010753: positive regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:EGL4

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE2

involved_in

GO:1902160: negative regulation of cyclic nucleotide-gated ion channel activity

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:A8WI01

P

  • has_input:(UniProtKB:A8WI01)
  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE2

involved_in

GO:0010753: positive regulation of cGMP-mediated signaling

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:A8WI01

P

Seeded From UniProt

complete

CAEEL:PDE2

involved_in

GO:0010753: positive regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:PDE2

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:CNG

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:CNG

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:G5EEE2

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:G5EEE2

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:CNG

involved_in

GO:0070482: response to oxygen levels

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

CAEEL:CNG

involved_in

GO:0010754: negative regulation of cGMP-mediated signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(WBbt:0004096)

Seeded From UniProt

complete

Notes

See also

References

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