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  • br NO GC pathway and implications for glaucoma

    2021-09-15


    NO-GC-1 pathway and implications for glaucoma Direct in vivo measurement of NO in the eye is not yet feasible. However, measurement of nitrate and nitrite levels are routinely used as markers for the activity of NOS and the production of NO radicals [98]. Several studies in human glaucoma patients suggest that various components of the NO-GC-1-cGMP pathway and its associated outcomes are linked to disease progression. Glaucoma patients exhibit decreased NO metabolite (nitrate/nitrite) and cGMP levels in AqH and plasma compared to patients without glaucoma [99,100]. This is accompanied by corresponding increases in the AqH level of l-Arginine, the amino TAE226 precursor of NO [101], and serum levels of l-arginine analogs, which are endogenous inhibitors of NOS or l-arginine uptake [102]. In eyes harvested posthumously from POAG patients, NADPH-diaphorase (NADPH-d) reactivity, a marker for NO production, is decreased in TM, SC and anterior longitudinal CM fibers [85]. NO production by cells of the SC may have a homeostatic function during IOP elevation, i.e. when the SC narrows and shear stress increases. Cells respond to increased IOP through increases in NO, which decreases contractility of the juxtacanalicular TM and increases the permeability of the SC inner wall in order to normalize IOP levels [77]. SC cells isolated from glaucomatous eyes are unresponsive to shear stress [77]. This suggests that the homeostatic feedback loop controlling NO synthesis is impaired in glaucoma and may contribute to elevations in IOP. Finally, NOS inhibition impairs blood flow in the optic nerve head of POAG patients to a greater extent than in healthy controls [103]. Taken together, these studies suggest an important role for the NO-GC-1 pathway and its downstream effector, cGMP, in glaucoma pathophysiology [64].
    NO-GC-1-cGMP pathway and disease mechanisms
    The NO-GC-1-cGMP pathway as a target for glaucoma therapeutics
    Conclusions The potential of the NO-GC-cGMP pathway to prevent and/or treat glaucoma underlies the development of NO-donor compounds as IOP lowering therapeutics. There are many benefits of targeting the NO-GC-cGMP pathway when developing novel therapeutics for glaucoma. NO increases AqH humor outflow through the conventional pathway, which aids in IOP reduction, whilst also increasing retinal perfusion and having putative neuroprotective effects (Fig. 4). The potential benefit in NO-releasing treatments is however offset by the delicate balance necessary to promote beneficial outcomes and avoid the negative consequences such as an induction of RNS, and other oxidative stressers. This leads to nitrate tolerance which can ultimately promote insensitivity to long-term NO exposure and inhibition on GC [256]. This risk is not alleviated by available NO donor compounds, which activate GC to produce cGMP.
    Introduction
    GCAP regulatory modes in zebrafish rods and cones
    Acknowledgement Experimental work done in the laboratory of the author is funded by several Grants of the Deutsche Forschungsgemeinschaft (DFG).
    Introduction Apicomplexan parasites are leading agents of infection in humans and animals worldwide. The diseases inflicted by these obligate-intracellular protozoans, including malaria and toxoplasmosis, are the result of tissue destruction and inflammation produced by lytic stages of parasite growth. The lytic life cycle occurs in four general steps: host cell attachment, host cell invasion, parasite replication, and host cell egress. Other than replication, all steps in this life cycle rely on timely secretion of proteins from apical organelles called micronemes (Carruthers and Tomley, 2008), presenting a functional bottleneck for parasite cell-to-cell transmission; however, it is unclear how microneme secretion is initiated. The current understanding of how micronemes are secreted largely stems from investigating signaling pathways downstream of their origination. It is well established that second messenger signaling drives microneme secretion; this includes calcium (Ca2+) (Carruthers and Sibley, 1999), phosphatidic acid (PA) (Bullen and Soldati-Favre, 2016), and purine cyclic nucleotides (cGMP and cAMP) (Ono et al., 2008, Wiersma et al., 2004). Cytosolic Ca2+ is kept at low levels by organelle sequestration during immotile replicative stages but elevated during processes such as egress, migration, and invasion (Lourido and Moreno, 2015). It has been proposed that IP3 produced from phosphoinositide phospholipase C (PI-PLC) cleavage of PIP2 opens an IP3-sensitive Ca2+ channel (Lovett et al., 2002), though such channels have eluded identification in apicomplexans (Garcia et al., 2017). Once released, cytosolic Ca2+ activates apicomplexan calcium-dependent protein kinases (CDPKs) (Billker et al., 2009, Lourido et al., 2010) and vesicle trafficking (Farrell et al., 2012) to promote microneme secretion. In addition to IP3/Ca2+, PI-PLC also produces DAG from PIP2 cleavage, which can be converted to PA by DAG kinase. PA is thought to play an important role in microneme secretion by interacting with a PA receptor on the micronemes themselves, called APH, priming micronemes for fusion with the plasma membrane (Bullen et al., 2016). PI-PLC function is regulated in part by inositol phosphate levels in Apicomplexa, which in turn are controlled by cGMP-dependent protein kinase (PKG) (Brochet et al., 2014). Importantly, PKG also controls a final step in microneme secretion as loss of PKG expression or activity cannot be overcome by systemically elevated Ca2+, PA, or cGMP (Brown et al., 2016, Brown et al., 2017, Bullen et al., 2016). For balance, cAMP-dependent protein kinase (PKA) has been proposed as a negative regulator of microneme secretion to prevent premature secretion and egress during parasite replication (Jia et al., 2017). Cyclic nucleotides are synthesized from nucleoside triphosphates by nucleotide cyclases. Genetic evidence exists for the importance of nucleotide cyclases in Plasmodium ookinetes and sporozoites (Hirai et al., 2006, Moon et al., 2009, Ono et al., 2008), yet it is unclear how these enzymes are regulated and whether they perform similar roles in other life stages or parasites.