Figure 2. Regulation of [Ca²⁺]_i homeostasis by Ca²⁺ binding proteins and kinases.

Regulation of Ca²⁺ homeostasis involves a multitude of Ca²⁺ binding proteins and enzymes, including CaMKII, PKC, PKA and S100A1: (1). CaMKII catalyzes phosphorylation of voltage-gated Ca²⁺ channels (mostly Ca_V1.2 in ventricle) to increase Ca²⁺ entry, RyR2 to increase Ca²⁺ release, voltage-gated Na⁺ channels (mostly Na_V1.5 in ventricle) to increase subsarcolemmal [Na+]_i,, which decreases the driving force for Ca²⁺ extrusion by the Na⁺/Ca²⁺ exchanger (NCX), and PLN to reduce the inhibitory activity of PLN on SERCA2a. In general, the increased phosphorylation of these proteins by CaMKII increases Ca²⁺ influx, and storage by the SR, which leads to increased systolic [Ca²⁺]_i and increased rate and magnitude of force (pressure) generation and improved lusitropy. (2) PKA is activated by β–AR agonists and catalyzes phosphorylation of the same Ca²⁺ regulatory proteins modified by CaMKII, but at different amino acids. (3) Classical PKC isoforms are activated downstream to a variety of G protein coupled receptors and are activated by increased [Ca²⁺]_i, leading to decreased activity SERCA2 by phosphorylating inhibitor 1 (I-1) resulting in PLN dephosphorylation, reducing SR Ca²⁺ load and Ca²⁺ release, causing reduced contractility. (4) S100A1 interacts with the SERCA2a/PLN complex in a Ca²⁺-dependent manner to augment SR Ca²⁺ uptake and increase SR Ca²⁺ content. S100A1 also directly regulates RyR2 function, stimulates ATP synthase activity and promotes the adenosine nucleotide translocator (ANT) function to increase ATP synthesis and mitochondrial ATP efflux in cardiomyocytes.