Intracellular Ca²⁺ cycling and associated signaling pathway in cardiomyocytes. On a beat-by-beat basis, a calcium transient is evoked by the initial influx of a small amount of Ca²⁺ through the LTCC and the subsequent large-scale Ca²⁺ release from the SR through the RyR. During diastole, cytosolic Ca²⁺ is taken up into the SR by the PLN-regulated SERCA2a pump. β receptor–mediated PKA stimulation regulates this Ca²⁺ cycling by phosphorylating LTCC, RyR, and PLN. In normal hearts, sympathetic stimulation activates β₁-adrenergic receptor, which in turn stimulates the production of cAMP by adenylyl cyclase and thereby activates PKA. PKA phosphorylates PLN and RyR, both of which contribute to an increased intracellular Ca²⁺ transient and enhanced cellular contractility (pink zone signal). PP1 and PP2A regulate the dephosphorylation process of these Ca²⁺ regulatory proteins (RyR, PLN, LTCC) (blue zone signaling). Activation of the Gαq-coupled receptors (angiotensin II receptor, endothelin 1 receptor, or α-adrenergic receptor) activates PLC, which in turn activates PKC-α. The PKC-α phosphorylates I-1, augmenting the activity of PP1 and causing hypophosphorylation of PLB. The PLB hypophosphorylation inhibits SERCA2a activity, thereby decreasing SR Ca²⁺ uptake. The increased Ca²⁺ level in the cytosol activates CAMKII, which affects the functions of RyR and PLN. Activation or deactivation of these molecules at a node in the signaling cascade affects beat-by-beat Ca²⁺ cycling, and such maneuvers have recently been highlighted as potential new therapeutic strategies against HF. α, G protein subunit α; β, G protein subunit β; γ, G protein subunit γ; AC, adenylyl cyclase; PLC, phospholipase C.