RRC ID 45174
Author Kotake M, Sato K, Mogi C, Tobo M, Aoki H, Ishizuka T, Sunaga N, Imai H, Kaira K, Hisada T, Yamada M, Okajima F.
Title Acidic pH increases cGMP accumulation through the OGR1/phospholipase C/Ca(2+)/neuronal NOS pathway in N1E-115 neuronal cells.
Journal Cell Signal
Abstract Neuronal NO synthase (nNOS)-mediated cGMP accumulation has been shown to affect a variety of neuronal cell activities, regardless of whether they are detrimental or beneficial, depending on the amount of their levels, under the physiological and pathological situations. In the present study, we examined the role of proton-sensing G protein-coupled receptors (GPCRs), which have been identified as new pH sensors, in the acidic pH-induced nNOS/cGMP activity in N1E-115 neuronal cells. In this cell line, ovarian cancer G protein-coupled receptor 1 (OGR1) and G protein-coupled receptor 4 (GPR4) mRNAs are expressed. An extracellular acidic pH increased cGMP accumulation, which was inhibited by nNOS-specific inhibitors. Acidic pH also activated phospholipase C/Ca(2+) pathways and Akt-induced phosphorylation of nNOS at S1412, both of which have been shown to be critical regulatory mechanisms for nNOS activation. The acidic pH-induced activation of the phospholipase C/Ca(2+) pathway, but not Akt/nNOS phosphorylation, was inhibited by small interfering RNA specific to OGR1 and YM-254890, an inhibitor of Gq/11 proteins, in association with the inhibition of cGMP accumulation. Moreover cGMP accumulation was inhibited by 2-aminoethoxydiphenyl borate, an inhibitor of inositol 1,4,5-trisphosphate channel; however, it was not by wortmannin, a phosphatidylinositol 3-kinase inhibitor, which inhibited Akt/nNOS phosphorylation. In conclusion, acidic pH stimulates cGMP accumulation preferentially through the OGR1/Gq/11 proteins/phospholipase C/Ca(2+)/nNOS in N1E-115 neuronal cells. Akt-mediated phosphorylation of nNOS, however, does not appreciably contribute to the acidification-induced accumulation of cGMP.
Volume 26(11)
Pages 2326-32
Published 2014-11-1
DOI 10.1016/j.cellsig.2014.07.010
PII S0898-6568(14)00229-0
PMID 25025574
MeSH Animals Calcium Signaling / drug effects Calcium Signaling / physiology* Cell Line, Tumor Cyclic GMP GTP-Binding Protein alpha Subunits, Gq-G11 / genetics GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism Hydrogen-Ion Concentration Mice Neurons / cytology Neurons / metabolism* Nitric Oxide Synthase Type I / antagonists & inhibitors Nitric Oxide Synthase Type I / genetics Nitric Oxide Synthase Type I / metabolism* Peptides, Cyclic / pharmacology Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / metabolism* Type C Phospholipases / genetics Type C Phospholipases / metabolism*
IF 3.968
Times Cited 6
Human and Animal Cells MG6(RCB2403)