Exp Mol Med.  2017 Jun;49(6):e341. 10.1038/emm.2017.68.

Protein tyrosine phosphatase 1B is a mediator of cyclic ADP ribose-induced Ca²⁺ signaling in ventricular myocytes

• Park SA
• Hong BZ
• Ha KC
• Kim UH
• Han MK
• Kwak YG

• KMID: 2386961
• DOI: http://doi.org/10.1038/emm.2017.68

Abstract

Cyclic ADP-ribose (cADPR) releases Ca²âº from ryanodine receptor (RyR)-sensitive calcium pools in various cell types. In cardiac myocytes, the physiological levels of cADPR transiently increase the amplitude and frequency of Ca²âº (that is, a rapid increase and decrease of calcium within one second) during the cardiac action potential. In this study, we demonstrated that cADPR levels higher than physiological levels induce a slow and gradual increase in the resting intracellular Ca²âº ([Ca²âº](i)) level over 10"‰min by inhibiting the sarcoendoplasmic reticulum Ca²âº ATPase (SERCA). Higher cADPR levels mediate the tyrosine-dephosphorylation of α-actin by protein tyrosine phosphatase 1B (PTP1B) present in the endoplasmic reticulum. The tyrosine dephosphorylation of α-actin dissociates phospholamban, the key regulator of SERCA, from α-actin and results in SERCA inhibition. The disruption of the integrity of α-actin by cytochalasin B and the inhibition of α-actin tyrosine dephosphorylation by a PTP1B inhibitor block cADPR-mediated Ca²âº increase. Our results suggest that levels of cADPR that are relatively higher than normal physiological levels modify calcium homeostasis through the dephosphorylation of α-actin by PTB1B and the subsequent inhibition of SERCA in cardiac myocytes.

MeSH Terms

Action Potentials
Adenosine Diphosphate*
Adenosine Triphosphatases
Calcium
Cyclic ADP-Ribose
Cytochalasin B
Endoplasmic Reticulum
Homeostasis
Muscle Cells*
Myocytes, Cardiac
Protein Tyrosine Phosphatase, Non-Receptor Type 1*
Protein Tyrosine Phosphatases*
Reticulum
Ryanodine Receptor Calcium Release Channel
Tyrosine
Adenosine Diphosphate
Adenosine Triphosphatases
Calcium
Cyclic ADP-Ribose
Cytochalasin B
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases
Ryanodine Receptor Calcium Release Channel
Tyrosine