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Int. J. Mol. Sci. 2018, 19(8), 2313; https://doi.org/10.3390/ijms19082313

cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators

1
Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany
2
Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, 44801 Bochum, Germany
3
Pharmakologisches Institut für Naturwissenschaftler, University of Frankfurt, 60438 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Received: 16 July 2018 / Revised: 1 August 2018 / Accepted: 4 August 2018 / Published: 7 August 2018
(This article belongs to the Special Issue cGMP-Signalling in Cells: Molecular and Functional Features)
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Abstract

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. View Full-Text
Keywords: Cyclic GMP; nitric oxide; guanylyl cyclase; NO-GC stimulators; Purkinje cells; cerebellar granule cells; striatum; hippocampal neurons; FRET imaging; transgenic mice Cyclic GMP; nitric oxide; guanylyl cyclase; NO-GC stimulators; Purkinje cells; cerebellar granule cells; striatum; hippocampal neurons; FRET imaging; transgenic mice
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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).
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Peters, S.; Paolillo, M.; Mergia, E.; Koesling, D.; Kennel, L.; Schmidtko, A.; Russwurm, M.; Feil, R. cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators. Int. J. Mol. Sci. 2018, 19, 2313.

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