TY  - JOUR
A1  - Peters, Stefanie
A1  - Paolillo, Michael
A1  - Mergia, Evanthia
A1  - Koesling, Doris
A1  - Kennel, Lea
A1  - Schmidtko, Achim
A1  - Russwurm, Michael
A1  - Feil, Robert
T1  - cGMP imaging in brain slices reveals brain region-specific activity of NO-sensitive Guanylyl Cyclases (NO-GCs) and NO-GC stimulators
T2  - International journal of molecular sciences
N2  - Impaired NO-cGMP signaling has been linked to several neurological disorders. NO-sensitive guanylyl cyclase (NO-GC), of which two isoforms—NO-GC1 and NO-GC2—are known, represents a promising drug target to increase cGMP in the brain. Drug-like small molecules have been discovered that work synergistically with NO to stimulate NO-GC activity. However, the effects of NO-GC stimulators in the brain are not well understood. In the present study, we used Förster/fluorescence resonance energy transfer (FRET)-based real-time imaging of cGMP in acute brain slices and primary neurons of cGMP sensor mice to comparatively assess the activity of two structurally different NO-GC stimulators, IWP-051 and BAY 41-2272, in the cerebellum, striatum and hippocampus. BAY 41-2272 potentiated an elevation of cGMP induced by the NO donor DEA/NO in all tested brain regions. Interestingly, IWP-051 potentiated DEA/NO-induced cGMP increases in the cerebellum and striatum, but not in the hippocampal CA1 area or primary hippocampal neurons. The brain-region-selective activity of IWP-051 suggested that it might act in a NO-GC isoform-selective manner. Results of mRNA in situ hybridization indicated that the cerebellum and striatum express NO-GC1 and NO-GC2, while the hippocampal CA1 area expresses mainly NO-GC2. IWP-051-potentiated DEA/NO-induced cGMP signals in the striatum of NO-GC2 knockout mice but was ineffective in the striatum of NO-GC1 knockout mice. These results indicate that IWP-051 preferentially stimulates NO-GC1 signaling in brain slices. Interestingly, no evidence for an isoform-specific effect of IWP-051 was observed when the cGMP-forming activity of whole brain homogenates was measured. This apparent discrepancy suggests that the method and conditions of cGMP measurement can influence results with NO-GC stimulators. Nevertheless, it is clear that NO-GC stimulators enhance cGMP signaling in the brain and should be further developed for the treatment of neurological diseases.
KW  - Cyclic GMP
KW  - nitric oxide
KW  - guanylyl cyclase
KW  - NO-GC stimulators
KW  - Purkinje cells
KW  - cerebellar granule cells
KW  - striatum
KW  - hippocampal neurons
KW  - FRET imaging
KW  - transgenic mice
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48487
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-484879
SN  - 1422-0067
SN  - 1661-6596
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
VL  - 19
IS  - 8, Art. 2313
SP  - 1
EP  - 20
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -