Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aquaporin 4 (AQP4) is the predominant water channel in the mammalian brain and is mainly expressed in the perivascular glial endfeet at the brain-blood interface. AQP4 has been described as an important entry and exit site for water during formation of brain edema and regulation of AQP4 is therefore of therapeutic interest. Phosphorylation of some aquaporins has been proposed to regulate their water permeability via gating of the channel itself. Protein kinase (PK)-dependent phosphorylation of Ser(111) has been reported to increase the water permeability of AQP4 expressed in an astrocytic cell line. This possibility was, however, questioned based on the crystal structure of the human AQP4. Our study aimed to resolve if Ser(111) was indeed a site involved in phosphorylation-mediated gating of AQP4. The water permeability of AQP4-expressing Xenopus oocytes was not altered by a range of activators and inhibitors of PKG and PKA. Mutation of Ser(111) to alanine or aspartate (to prevent or mimic phosphorylation) did not change the water permeability of AQP4. PKG activation had no effect on the water permeability of AQP4 in primary cultures of rat astrocytes. Molecular dynamics simulations of a phosphorylation of AQP4.Ser(111) recorded no phosphorylation-induced change in water permeability. A phospho-specific antibody, exclusively recognizing AQP4 when phosphorylated on Ser(111) , failed to detect phosphorylation in cell lysate of rat brain stimulated by conditions proposed to induce phosphorylation of this residue. Thus, our data indicate a lack of phosphorylation of Ser(111) and of phosphorylation-dependent gating of AQP4.
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PMID:Phosphorylation of rat aquaporin-4 at Ser(111) is not required for channel gating. 2361 25

Cerebral ischemia, followed by brain edema, can be life-threatening. It has been widely reported that matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP4) have prominent roles in the development of brain edema. However, the exact mechanisms by which MMP-9 and AQP4 influence brain edema are not fully understood. In this study, astrocytes were subjected to oxygen-glucose deprivation (OGD) /reperfusion (OGD/R) injury, an in vitro model of Ischemia/reperfusion (I/R). Cell viability was evaluated through the measurement of LDH release. The expression of MMP-9 and AQP4 also were measured by qPCR and western blot. Subsequently, we knocked out the MMP-9 gene using MMP-9 siRNA. AQP4 and its gene expression, and the LDH release rate were measured using ELISA, Western blotting, and RT-PCR. We also assessed cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), protein kinase C (PKC), and Ca2+/calmodulin-dependent protein kinase II (CaMK II) in MMP-9 knockout astrocytes. All measurements were performed with or without an OGD/R challenge. OGD/reperfusion enhanced LDH release levels, and also increased MMP-9 and AQP4 expression in astrocytes. Silencing the MMP-9 gene decreased LDH release levels, and also was associated with decreased AQP4 expression. The expression of PKC, but not PKA, PKG, or CaMK II, was decreased. This study revealed that OGD/reperfusion could cause cell damage in vitro. MMP-9 silencing protected astrocytes from hypoxic insult, and the protective effect may be enhanced by the downregulation of AQP4 expression. In conclusion, downregulating MMP-9 expression may be useful for the prevention and treatment of brain ischemia.
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PMID:Silencing matrix metalloproteinase 9 exerts a protective effect on astrocytes after oxygen-glucose deprivation and is correlated with suppression of aquaporin-4. 3245 Jan 87