Kreitmeier, K. G. and Tarnowski, D. and Nanadikar, M. S. and Baier, M. J. and Wagner, S. and Katschinski, D. M. and Maier, L. S. and Sag, C. M. (2021) CaMKII delta Met281/282 oxidation is not required for recovery of calcium transients during acidosis. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 320 (3). H1199-H1212. ISSN 0363-6135, 1522-1539
Full text not available from this repository. (Request a copy)Abstract
CaMKII is needed for the recovery of Ca2+ transients during acidosis but also mediates postacidic arrhythmias. CaMKIIS can sustain its activity following Met281/282 oxidation. Increasing cytosolic Na+ during acidosis as well as postacidic pH normalization should result in prooxidant conditions within the cell favoring oxidative CaMKII delta activation. We tested whether CaMKII delta activation through Met281/282 oxidation is involved in recovery of Ca2+ transients during acidosis and promotes cellular arrhythmias post-acidosis. Single cardiac myocytes were isolated from a well-established mouse model in which CaMKIIS was made resistant to oxidative activation by knock-in replacement of two oxidant-sensitive methionines (Met281/282) with valines (MM-VV). MM-W myocytes were exposed to extracellular acidosis (pH(o) 6.5) and compared to wild type (WT) control cells. Full recovery of Ca2+ transients was observed in both WT and MM-W cardiac myocytes during late-phase acidosis. This was associated with comparably enhanced sarcoplasmic reticulum Ca2+ load and preserved CaMKII specific phosphorylation of phospholamban at Thr17 in MM-W myocytes. CaMKII was phosphorylated at Thr287, but not Met281/282 oxidized. In line with this, postacidic cellular arrhythmias occurred to a similar extent in WT and MM-W cells, whereas inhibition of CaMKII using AIP completely prevented recovery of Ca2+ transients during acidosis and attenuated postacidic arrhythmias in MM-W cells. Using genetically altered cardiomyocytes with cytosolic expression of redox-sensitive green fluorescent protein-2 coupled to glutaredoxin 1, we found that acidosis has a reductive effect within the cytosol of cardiac myocytes despite a significant acidosis-related increase in cytosolic Na+. Our study shows that activation of CaMKIIS through Met281/282 oxidation is neither required for recovery of Ca2+ transients during acidosis nor relevant for postacidic arrhythmogenesis in isolated cardiac myocytes. Acidosis reduces the cytosolic glutathione redox state of isolated cardiac myocytes despite a significant increase in cytosolic Na+. Pharmacological inhibition of global CaMKII activity completely prevents recovery of Ca2+ transients and protects from postacidic arrhythmias in MM-W myocytes, which confirms the relevance of CaMKII in the context of acidosis. NEW & NOTEWORTHY The current study shows that activation of CaMKII delta through Met281/282 oxidation is neither required for CaMKII-dependent recovery of Ca2+ transients during acidosis nor relevant for the occurrence of postacidic cellular arrhythmias. Despite a usually prooxidant increase in cytosolic Na+ acidosis reduces the cytosolic glutathione redox state within cardiac myocytes. This novel finding suggests that oxidation of cytosolic proteins is less likely to occur during acidosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; SR CA2+ LOAD; SARCOPLASMIC-RETICULUM; INTRACELLULAR PH; CONTRACTILE RECOVERY; PHOSPHOLAMBAN; ACTIVATION; HEART; PHOSPHORYLATION; ARRHYTHMIAS; acidosis; calcium signaling; CaMKII; excitation-contraction coupling; redox signaling |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Aug 2022 09:47 |
| Last Modified: | 02 Aug 2022 09:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45996 |
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