FIGURE 2.

Alcohol action on cardiomyocyte contractility. E-C coupling in cardiomyocytes occurs via calcium-induced calcium release (CICR). DHPRs are activated by depolarization of the cardiac myocyte membrane (sarcolemma) causing them to release a small amount of Ca²⁺ into the cytoplasm. This Ca²⁺ then activates RyR2, leading to Ca²⁺ influx from SR stores and an exponential increase in the intracellular Ca²⁺ concentration. Ca²⁺ then binds and activates troponin C which activates tropomyosin, allowing the physical interaction between myosin and actin. The points of interaction between these two contractile proteins are called “cross bridges” and allow myosin heads to slide across actin filaments, resulting in a “power stroke” and myocyte contraction. Both acute and chronic alcohol consumption lead to negative inotropic effects (diminished contractility). The effects of acute ethanol consumption/administration include: decreased proteostasis (decreased protein synthesis and altered function etc.), increased ROS production and oxidative stress, decreased Ca²⁺ handling (see main text), increased SERCA activity and increased NO^• production. NOX2 signaling and CAMKII activity were shown to be involved in ethanol-induced increase in ROS production. Chronic ethanol consumption/administration exacerbates these effects. In addition, other effects are observed such as increased autophagy and significantly decreased protein levels of SERCA, NCX, CYP-2E1, iNOS and PLB. The significant increase in ROS production and oxidative stress was shown to be linked to the ethanol-mediated upregulation of JNK2 and ASK-1 signaling pathways. These alcohol-induced negative inotropic events serve to reduce cardiac contractility and increase susceptibility to the development of various cardiomyopathies such as AF. Abbreviations: ASK-1, Apoptosis signal-regulating kinase 1; CAMKII, Ca²⁺ calmodulin-dependent protein kinase II; DHPRs, dihydropyridine receptors; JNK2, c-Jun NH (2)-terminal kinase; NCX, Na⁺/Ca²⁺-exchanger; PKA, protein kinase A; PLB, phospholamban; PP1, protein phosphatase 1; ROS, reactive oxygen species; RyR, ryanodine receptors; SERCA, SR Ca²⁺ transport ATP-ase; SR, sarcoplasmic reticulum; t-tubules, transverse tubules.