Okadaic acid, a protein phosphatase inhibitor, increases the calcium transients in isolated ferret ventricular muscle

Lee, Anna; Takai, Akira; Dg, Allen

doi:10.1113/expphysiol.1991.sp003495

Cited by 7 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CaMKII autophosphorylation was only observed when phosphatase 1 was inhibited, but then pacing strongly enhanced autophosphorylation. The increase in CaMKII autophosphorylation is likely due to direct inhibition of phosphatases dephosphorylating CaMKII, but it is also possible that phosphatase inhibition enhances CaMKII activation by increasing [Ca 2+ ] i (via an increase in the phosphorylation level of Ca 2+ -regulatory proteins; [38][39][40] We also show however that in the presence of okadaic acid the RyR Ser-2814 was the first site significantly increased in response to pacing, not global CaMKII Thr-287. This does not rule out that CaMKII specifically associated with the RyR does become significantly transiently activated and/or autophosphorylated sooner, especially when considering that the local [Ca 2+ ] around the RyR in the junctional cleft might reach very high concentrations during each excitation-contraction cycle [41][42][43].…”

Section: Does Pacing Activate Camkii and Increase Autophosphorylation?mentioning

confidence: 81%

Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII

Huke

Bers

2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Frequency-dependent acceleration of relaxation (FDAR) is an important intrinsic mechanism that allows for diastolic filling of the ventricle at higher heart rates, yet its molecular mechanism is still not understood. Previous studies showed that FDAR is dependent on functional sarcoplasmic reticulum (SR) and can be abolished by phosphatase or by Ca/CaM kinase (CaMKII) inhibition. Additionally, CaMKII activity/autophosphorylation has been shown to be frequency-dependent. Thus, we tested the hypothesis that CaMKII phosphorylation of SR Ca 2+ -handling proteins (Phospholamban (PLB), Ca 2+ release channel (RyR)) mediates FDAR. Here we show that FDAR occurs abruptly in fluo-4 loaded isolated rat ventricular myocytes when frequency is raised from 0.1 to 2 Hz. The effect is essentially complete within four beats (2 s) with the τ of [Ca 2+ ] i decline decreasing by 42±3%. While there is a detectable increase in PLB Thr-17 and RyR Ser-2814 phosphorylation, the increase is quantitatively small (PLB<5%, RyR~8%) and the time-course is clearly delayed with regard to FDAR. The low substrate phosphorylation indicates that pacing of myocytes only mildly activates CaMKII and consistent with this CaMKIIδ autophosphorylation did not increase with pacing alone. However, in the presence of phosphatase 1 inhibition pacing triggered a net-increase in autophosphorylated CaMKII and also greatly enhanced PLB and RyR phosphorylation. We conclude that FDAR does not rely on phosphorylation of PLB or RyR. Even though CaMKII does become activated when myocytes are paced, phosphatases immediately antagonize CaMKII action, limit substrate phosphorylation and also prevent sustained CaMKII autophosphorylation (thereby suppressing global CaMKII effects).

show abstract

Section: Does Pacing Activate Camkii and Increase Autophosphorylation?mentioning

confidence: 81%

Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII

Huke

Bers

2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…This effect was accompanied by accelerated relaxation. Under the same conditions, PLB phosphorylation and free intracellular Ca 2+ were enhanced, which could explain the higher contractility [39,40]. Additional evidence for a role of PP1 in the control of cardiac function comes from the observations that PP1 activity is increased [13] and the level and phosphorylation state of I-1 is decreased [41] in human failing hearts.…”

Section: Discussionmentioning

confidence: 91%

Enhanced cardiac function in mice overexpressing protein phosphatase Inhibitor-2

Kirchhefer

Baba²,

Boknı́k

et al. 2005

Cardiovascular Research

View full text Add to dashboard Cite

show abstract

“…Therefore, we present here only data on electrically driven papillary muscles. Others have shown that these preparations exhibit changes in intracellular Ca 2ϩ (21) that are increased by PP inhibitors (12). Figure 2 depicts original tracings of single contractions in electrically driven guinea pig papillary muscles at high time resolution.…”

Section: Resultsmentioning

confidence: 99%

Role of protein phosphatases in regulation of cardiac inotropy and relaxation

Boknı́k

Khorchidi

Bodor

et al. 2001

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

We studied the effects of the protein phosphatase (PP) inhibitor cantharidin (Cant) on time parameters and force of contraction (FOC) in isometrically contracting electrically driven guinea pig papillary muscles. We correlated the mechanical parameters of contractility with phosphorylation of the inhibitory subunit of troponin (TnI-P) and with the site-specific phosphorylation of phospholamban (PLB) at serine-16 (PLB-Ser-16) and threonine-17 (PLB-Thr-17). Cant (after 30 min) started to increase FOC (112 +/- 4% of control, n = 10) and TnI-P and PLB-Thr-17 (120 +/- 5 and 128 +/- 7% of control) without any alteration of relaxation time. Cant (10 microM) started to increase PLB-Ser-16, but the relaxation was shortened at only 100 microM (from 140 +/- 9 to 116 +/- 12 ms, n = 9). Moreover, 100 microM Cant, 3 min after application, started to increase PLB-Thr-17, TnI-P, and FOC. Cant (100 microM) began to increase PLB-Ser-16 after 20 min. This was accompanied by shortening of relaxation time. Differences in protein kinase activation or different substrate specificities of PP may explain the difference in Cant-induced site-specific phosphorylation of PLB in isometrically contracting papillary muscles. Moreover, PLB-Thr-17 may be important for inotropy, whereas PLB-Ser-16 could be a major determinant of relaxation time.

show abstract

Okadaic acid, a protein phosphatase inhibitor, increases the calcium transients in isolated ferret ventricular muscle

Cited by 7 publications

References 10 publications

Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII

Temporal dissociation of frequency-dependent acceleration of relaxation and protein phosphorylation by CaMKII

Enhanced cardiac function in mice overexpressing protein phosphatase Inhibitor-2

Role of protein phosphatases in regulation of cardiac inotropy and relaxation

Contact Info

Product

Resources

About