The L-type calcium channel in the heart: the beat goes on
J. Clin. Invest. Ilona Bodi, et al. 115:3306 doi:10.1172/JCI27167 [Go to this article.]

Figure 1
A model illustrating the Ca²⁺ signaling pathways implicated in hypertrophy and heart failure. Stimulation of the β1-AR activates G_s (stimulatory G protein),, which activates adenylyl cyclase (AC), causing production of cAMP. This stimulates cAMP-dependent PKA, which phosphorylates (P) and alters the function of numerous substrates important for SR Ca²⁺ regulation, including the L-VDCC, RyR2, and phospholamban (PLN). β₂-ARs couple Gi/Ras/MEK1/2/ERK1/2 pathways to hypertrophy (G_i, inhibitory G protein; MEK1/2, mitogen-activated protein kinase kinase). Subsequently, the activated β1-AR is desensitized when it is phosphorylated by β-AR kinase-1 (βARK1). During hypertrophy, β₁-AR expression increases. In heart failure, while the levels of PLN protein expression remain unchanged (or decreased), the phosphorylation status at Ser16 and Thr17 is decreased, even though the levels of SR Ca²⁺-ATPase 2a (SERCA2a) are decreased. Cardiac SR-associated protein phosphatase-1 (PP-1) removes phosphate at Ser16 in PLN and is upregulated in heart failure. Calstabin2 (FKB12.6) plays a role in stabilizing RyR2 in order to help maintain the channel in a closed state during diastole. RyR2 is hyperphosphorylated in heart failure, and calstabin2 dissociates from RyR2. Elevated NCX is an adaptive change in heart failure that becomes maladaptive and may be responsible for both arrhythmogenesis and contractile dysfunction. PKC-α expression and activity are elevated in heart failure. Calcineurin (CN) is activated by sustained elevation of [Ca²⁺]_i. It dephosphorylates nuclear factor of activated T cells (NFAT), enabling its translocation to the nucleus, which is sufficient to induce hypertrophy. Hypertrophic stimuli, such as α1-adrenergic agonists, Ang II, and endothelin-1 (ET-1), all elevate [Ca²⁺]_i and activate the CN-NFAT, Ca²⁺/CaM-CaMKII, and PKC-MAPK-NFAT signaling systems through G protein–coupled receptors (GPCRs) and PLC-DAG-IP₃–dependent Ca²⁺ release [PLC, phospholipase C; DAG, diacylglycerol, IP₃, inositol (1,4,5)-trisphosphate]. Transcription factors, such as myocyte-enhancer factor 2 (MEF2) and GATA4 (cardiac zinc finger transcription factor) are located in the nucleus and serve as endpoints for hypertrophic-signaling pathways. AT₁, type 1 angiotensin II receptors; G_iβγ, βγ subunit of the activated Gi-binding protein; G_q, heterotrimeric GTP-binding protein, consisting of G_α and G_βγ, which dissociate upon receptor activation; NHE, Na⁺/H⁺ exchanger, regulates cytosolic pH; PIP₂, phosphatidylinositol 4,5-biphosphate; T tubule, transverse tubule.