br Future perspectives sGC signaling

Future perspectives sGC signaling is important in the maintenance of multiple physiological functions. sGC is localized to cell membranes with both sGC Cys modifications and heme regulation identified as the crucial components in regulating sGC activity. Specifically, S-nitrosation of several combinations of sGC Cys residues has been shown to both activate and inactivate sGC signaling. However, further studies are needed to gain a full understanding of the how and where of Cys modifications, the number of Cys modifications, and what possible other Cys modifications are needed to influence physiological changes and sGC stability and function (Fig. 4). Comparatively, sGC heme redox regulation has been more extensively studied. It is well established that oxidative stress can cause the oxidation of the sGC heme iron (Fe3+) resulting in desensitization to NO signaling and impaired vasorelaxation. Cyb5R3 has been shown to reduce the sGC oxidized heme iron to its NO-sensitive state (Fe2+). Yet, most of this work has been conducted in in vitro systems, making it imperative to explore the in vivo regulation of the sGC heme iron and to determine if other c-Myc Peptide or endogenous small molecules exist that can regulate sGC heme state. Moreover, it is worth considering that sGC cycling and association with different microdomains may be important for its signaling and stability. Lastly, therapeutic targeting of sGC via stimulators and activators not only provide mechanistic insight into sGC function but hold clinical potential for alleviating conditions such as hypertension.
Acknowledgements Funds were provided by National Institutes of Health Grants R01 HL 133864, R01 HL 128304, American Heart Association (AHA) Grant-in-Aid 16GRNT27250146 (ACS). Additionally, other support was provided by the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania (ACS).
Main Text Guanylyl cyclases (GCs) catalyse the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP) and pyrophosphate, and are key components of signal transduction cascades. cGMP levels regulate signalling cascades through various effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. These effectors are involved in the regulation of numerous processes, including vascular smooth-muscle motility, intestinal fluid homeostasis, and retinal phototransduction. GCs exist in two main forms in well-studied metazoans, yeasts and plants. The receptor form displays a single membrane-spanning domain that binds directly to extracellular ligands such as peptide hormones, whereas the soluble cytosolic forms are activated by membrane-soluble nitric oxide [1]. GCs have also been identified in more basal eukaryotic lineages such as Tetrahymena, Paramecium, Dictyostelium and Plasmodium [2]. These ‘atypical’ multimembrane spanning GCs contain two cyclase domains that are inversely arranged in a topology similar to that of mammalian adenylyl cyclases. Protozoan GCs additionally contain an amino-terminal P4-type ATPase-like domain, the function of which remains elusive [3]. A new study by Gao et al. [4] in this issue of Current Biology brings new insight into the function of this atypical GC topology, showing that it is required for the correct spatiotemporal synthesis of cGMP during the early stages of malaria transmission to mosquitoes [4]. Malaria is a major public health problem caused by Plasmodium parasites and transmitted by female Anopheles mosquitoes. Malaria parasites critically depend on an unusual form of gliding motility to colonise their hosts and invade cells. Transmission of malaria to the mosquito, for instance, relies on the ability of the motile zygote, the ookinete, to glide towards and invade the midgut epithelium (Figure 1A). One of the two Plasmodium GCs, GCβ, was previously shown to be essential for ookinete gliding through the activation of the cGMP-dependent protein kinase G 5, 6, 7. However, the geography of cGMP signalling remained elusive. In the new work, Gao and colleagues [4] studied the molecular function of GCβ in P. yoelii, a causal agent of rodent malaria and a genetically tractable model whose complete life cycle can be readily studied under laboratory conditions. Remarkably, the use of a CRISPR/Cas9 approach that was recently implemented in P. yoelii by the same group [8] raised the bar for experimental genetics in this parasite and generated an impressively large number of genetically modified parasite lines for further study.