SERCA is critical to control the Bowditch effect in the heart

Abstract

The Bowditch effect or staircase phenomenon is the increment or reduction of contractile force when heart rate increases, defined as either a positive or negative staircase. The healthy and failing human heart both show positive or negative staircase, respectively, but the causes of these distinct cardiac responses are unclear. Different experimental approaches indicate that while the level of Ca2+ in the sarcoplasmic reticulum is critical, the molecular mechanisms are unclear. Here, we demonstrate that Drosophila melanogaster shows a negative staircase which is associated to a slight but significant frequency-dependent acceleration of relaxation (FDAR) at the highest stimulation frequencies tested. We further showed that the type of staircase is oppositely modified by two distinct SERCA mutations. The dominant conditional mutation SERCAA617T induced positive staircase and arrhythmia, while SERCAE442K accentuated the negative staircase of wild type. At the stimulation frequencies tested, no significant FDAR could be appreciated in mutant flies. The present results provide evidence that two individual mutations directly modify the type of staircase occurring within the heart and suggest an important role of SERCA in regulating the Bowditch effect.

Inhalation of marijuana affects Drosophila heart function

“…2D shows that wall shortening increased significantly after prolonged inhalation of Cannabis sp extracts (11-13 days). Although at first sight this positive inotropic response may be related to the slowdown of heart rate (9), contractility in the T&I group is similar to the control, in spite that heart rate remains reduced. Moreover, we previously observed that increasing heart rate reduces Ca 2+ transient with minimal effects on wall shortening (9), an opposite pattern to the one described here for cannabinoids.…”

“…Although at first sight this positive inotropic response may be related to the slowdown of heart rate (9), contractility in the T&I group is similar to the control, in spite that heart rate remains reduced. Moreover, we previously observed that increasing heart rate reduces Ca 2+ transient with minimal effects on wall shortening (9), an opposite pattern to the one described here for cannabinoids. Therefore, these results would suggest that the increase in contractility observed in the 11-13 treated flies might be mediated by mechanism different from heart rate reduction.…”

“…A reporter system that express the green fluorescent protein (GFP) in cardiac and pericardial cells was used to track the movement of a cardiac or pericardial cell during each cardiac cycle (systole and diastole). Mechanical parameters were defined as previously described (9). Fig Interestingly, heart rate reduction was significantly higher in flies in which treatment was interrupted for 5 days after 5 days of treatment (indicated as T & I in Fig.…”

Luteolin modulates SERCA2a via Sp1 upregulation to attenuate myocardial ischemia/reperfusion injury in mice

“…SERCA2a, Na + –Ca 2+ exchangers, L-type calcium channels, ryanodine receptors and other molecules too numerous to mention here 30 . Previous studies have recorded the significance of SERCA2a in this pathology 31 , 32 . It is now accepted that SERCA2a plays a crucial role in regulating spatial and temporal homeostasis of Ca 2+ in cardiomyocytes.…”

Targeting Calcium Homeostasis in Myocardial Ischemia/Reperfusion Injury: An Overview of Regulatory Mechanisms and Therapeutic Reagents

“…SERCA1 is mainly expressed in fasttwitch skeletal muscle, SERCA2b mainly in smooth muscle and non-muscle tissue, SERCA2c mainly in epithelial and hematopoietic cells and SERCA3 primarily in hematopoietic cells (Lipskaia et al, 2014). SERCA has a molecular weight of 110 kDa and hydrolyzes one ATP to transport two Ca 2+ back to the SR, causing myocardial relaxation (Balcazar et al, 2018). SERCA consists of three distinct domains, including the cytoplasmic head, the transmembrane region of ten helical segments that contain two Ca 2+ binding sites, and luminal loops (Stammers et al, 2015).…”