| First Author | Müller PM | Year | 2012 |
| Journal | Free Radic Biol Med | Volume | 53 |
| Issue | 8 | Pages | 1574-83 |
| PubMed ID | 22922339 | Mgi Jnum | J:190043 |
| Mgi Id | MGI:5447879 | Doi | 10.1016/j.freeradbiomed.2012.08.011 |
| Citation | Muller PM, et al. (2012) H(2)O(2) lowers the cytosolic Ca(2)(+) concentration via activation of cGMP-dependent protein kinase Ialpha. Free Radic Biol Med 53(8):1574-83 |
| abstractText | The cGMP-dependent protein kinase I (cGKI) is a key mediator of cGMP signaling, but the specific functions of its two isoforms, cGKIalpha and cGKIbeta, are poorly understood. Recent studies indicated a novel cGMP-independent role for cGKIalpha in redox sensing. To dissect the effects of oxidative stress on the cGKI isoforms, we used mouse embryonic fibroblasts and vascular smooth muscle cells (VSMCs) expressing both, one, or none of them. In cGKIalpha-expressing cells, but not in cells expressing only cGKIbeta, incubation with H(2)O(2) induced the formation of a disulfide bond between the two identical subunits of the dimeric enzyme. Oxidation of cGKIalpha was associated with increased phosphorylation of its substrate, vasodilator-stimulated phosphoprotein. H(2)O(2) did not stimulate cGMP production, indicating that it activates cGKIalpha directly via oxidation. Interestingly, there was a mutual influence of H(2)O(2) and cGMP on cGKI activity and disulfide bond formation, respectively; preoxidation of the kinase with H(2)O(2) slightly impaired its activation by cGMP, whereas preactivation of the enzyme with cGMP attenuated its oxidation by H(2)O(2). To evaluate the functional relevance of the noncanonical H(2)O(2)-cGKIalpha pathway, we studied the regulation of the cytosolic Ca(2)(+) concentration ([Ca(2)(+)](i)). H(2)O(2) suppressed norepinephrine-induced Ca(2)(+) transients in cGKIalpha-expressing VSMCs and, to a lower extent, in VSMCs expressing only cGKIbeta or none of the isoforms. Thus, H(2)O(2) lowers [Ca(2)(+)](i) mainly via a cGKIalpha-dependent pathway. These results indicate that oxidative stress selectively targets the cGKIalpha isoform, which then modulates cellular processes in a cGMP-independent manner. A decrease in [Ca(2)(+)](i) in VSMCs via activation of cGKIalpha might be a major mechanism of H(2)O(2)-induced vasodilation. |
