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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.
Highlights
The second messenger cyclic 3’,5’-guanosine monophosphate regulates various physiological processes such as cellular growth and contractility, cardiovascular homeostasis, inflammation, sensory transduction, and neuronal plasticity and learning [1,2]. cGMP is generated from GTP by either nitric oxide (NO)-sensitive guanylyl cyclases (NO-GCs) [3,4] or membrane-bound particulate guanylyl cyclases that are activated by peptides like the natriuretic peptides, guanylin/uroguanylin, or enterotoxins [5]
Application of NO to our brain slices resulted in robust cGMP increases in Purkinje cells and granule neurons of the cerebellum, the striatum and the hippocampal CA1 area
These results are in line with previous work showing the presence of the NO-cGMP signaling pathway in these brain regions [35,43,44,45,46,47]
Summary
The second messenger cyclic 3’,5’-guanosine monophosphate (cGMP) regulates various physiological processes such as cellular growth and contractility, cardiovascular homeostasis, inflammation, sensory transduction, and neuronal plasticity and learning [1,2]. cGMP is generated from GTP by either nitric oxide (NO)-sensitive guanylyl cyclases (NO-GCs) [3,4] or membrane-bound particulate guanylyl cyclases that are activated by peptides like the natriuretic peptides, guanylin/uroguanylin, or enterotoxins [5]. CGMP is generated from GTP by either nitric oxide (NO)-sensitive guanylyl cyclases (NO-GCs) [3,4] or membrane-bound particulate guanylyl cyclases that are activated by peptides like the natriuretic peptides, guanylin/uroguanylin, or enterotoxins [5]. The prosthetic heme group of NO-GC is bound to the β1 subunit through the axial ligand histidine 105 [7] and the heme-binding motif tyrosine 135 and arginine 139 [8]. NO binding to the heme Fe2+ leads to the formation of nitrosyl heme [9]. This disrupts the histidine 105-iron bond and is required but not sufficient for activation of the enzyme [7,10,11,12]. CGMP acts on several downstream effectors including cyclic nucleotide-gated ion channels, cGMP-dependent protein kinases, and phosphodiesterases (PDEs) that degrade cAMP and/or cGMP [2]
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