The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) pump: a potential target for intervention in aging and skeletal muscle pathologies

As a key regulator of cellular calcium homeostasis, the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump acts to transport calcium ions from the cytosol back to the sarcoplasmic reticulum (SR) following muscle contraction. SERCA function is closely associated with muscle health and function, and SERCA activity is susceptible to muscle pathogenesis. For example, it has been well reported that pathological conditions associated with aging, neurodegeneration, and muscular dystrophy (MD) significantly depress SERCA function with the potential to impair intracellular calcium homeostasis and further contribute to muscle atrophy and weakness. As a result, targeting SERCA activity has attracted attention as a therapeutical method for the treatment of muscle pathologies. The interventions include activation of SERCA activity and genetic overexpression of SERCA. This review will focus on SERCA function and regulation mechanisms and describe how those mechanisms are affected under muscle pathological conditions including elevated oxidative stress induced by aging, muscle disease, or neuromuscular disorders. We also discuss the current progress and therapeutic approaches to targeting SERCA in vivo.

Plasma Membrane Calcium ATPase Regulates Stoichiometry of CD4+ T-Cell Compartments

Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca2+ levels are essential for balanced immune outcomes. How Ca2+ contributes to regulating compartment stoichiometry is unknown. Here, we show that plasma membrane Ca2+ ATPase 4 (PMCA4) is differentially expressed in human CD4+ T compartments yielding distinct store operated Ca2+ entry (SOCE) profiles. Modulation of PMCA4 yielded a more prominent increase of SOCE in memory than in naïve CD4+ T cell. Interestingly, downregulation of PMCA4 reduced the effector compartment fraction and led to accumulation of cells in the naïve compartment. In silico analysis and chromatin immunoprecipitation point towards Ying Yang 1 (YY1) as a transcription factor regulating PMCA4 expression. Analyses of PMCA and YY1 expression patterns following activation and of PMCA promoter activity following downregulation of YY1 highlight repressive role of YY1 on PMCA expression. Our findings show that PMCA4 adapts Ca2+ levels to cellular requirements during effector and quiescent phases and thereby represent a potential target to intervene with the outcome of the immune response.

PMCA4 inhibition does not affect cardiac remodelling following myocardial infarction, but may reduce susceptibility to arrhythmia

Ischaemic heart disease is the world’s leading cause of mortality. Survival rates from acute myocardial infarction (MI) have improved in recent years; however, this has led to an increase in the prevalence of heart failure (HF) due to chronic remodelling of the infarcted myocardium, for which treatment options remain poor. We have previously shown that inhibition of isoform 4 of the plasma membrane calcium ATPase (PMCA4) prevents chronic remodelling and HF development during pressure overload, through fibroblast mediated Wnt signalling modulation. Given that Wnt signalling also plays a prominent role during remodelling of the infarcted heart, this study investigated the effect of genetic and functional loss of PMCA4 on cardiac outcomes following MI. Neither genetic deletion nor pharmacological inhibition of PMCA4 affected chronic remodelling of the post-MI myocardium. This was the case when PMCA4 was deleted globally, or specifically from cardiomyocytes or fibroblasts. PMCA4-ablated hearts were however less prone to acute arrhythmic events, which may offer a slight survival benefit. Overall, this study demonstrates that PMCA4 inhibition does not affect chronic outcomes following MI.

Modulating the mechanokinetics of spontaneous contractions of the myometrium of rats using calix[4]arene C-90 – plasma membrane calcium ATPase inhibitor

Introduction. Plasma membrane calcium ATPase is a constitutive structure of cells that functions as a high affinity system of releasing Са2+ ions from the cytoplasm and ensures a long-term maintenance of the basal concentration of these cations in the state of dormancy. Currently, there are no satisfactory means for the pharmacological correction of plasma membrane calcium ATPase function. Thus, elaboration, synthesis, and study of substances with the targeted impact on plasma membrane calcium ATPase are topical issues. Previously, we determined the ability of this calix[4]arene in the concentration of 10 µM to inhibit the contractive activity and to slow down the relaxation of smooth muscle of the myometrium in the NO-dependent way, which considerably decreases the normalized maximal velocity of the relaxation phase. Materials and Methods. The tenzometric methods and mechanokinetic analysis were used to investigate the impact of the cumulative increase in the concentration of calix[4]arene С-90 (10 nM – 100 µM) on the spontaneous contractive activity of the myometrium of rats. The complete profile of spontaneous cycles of contractions-relaxa­tions was studied by the empirical multiparameter method of complex mechanokinetic analysis, elaborated by us (with the consideration of the parameters of time (τ0, τC and τR), force (Fmax, FC and FR), velocity (VC and VR), and impulse (Іmax, ІC and ІR). Results. Calix[4]arene C-90 evoked the dose-dependent inhibition of spontaneous contractive activity of the myometrium preparations. Its high concentrations caused a change in the structure of the contraction act, such as an increase in the duration of the contraction phase, while the duration of the relaxation phase did not show any changes. The multiparameter method of the complex mechanokinetic analysis demonstrated that in the whole range of the investigated concentrations, substance С-90 considerably decreases the indices of force parameters (Fmax, FC and FR) and the values of impulses of force Іmax, IC and IR of the spontaneous contractions of the myometrium. On the background of all the applied concentrations (10-7–10-4 М), calix[4]arene С-90 conditioned the slowing down of the relaxation of spontaneous contractions in uterine muscle prepa­rations of rats, which was reflected in a reliable decrease in the parameter for the maxi­mal velocity of the relaxation phase (VR). Conclusions. The results of the study demonstrate that calix[4]arene С-90 inhibits the processes of Са2+ extrusion from smooth muscle cells myoplasm, probably, impacting plasma membrane calcium ATPase molecules directly. It is noteworthy that C-90 is also likely to inhibit the processes of the intake of these cations to cells from the extracellular medium, causing a decrease in the velocity of force intensification during the contraction phase, and reducing the frequency and force of the spontaneous contractions in the myometrium.