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Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte

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Calcium (Ca2+) plays many important regulatory roles in cardiac muscle cells. In the initial phase of the action potential, influx of Ca2+ through sarcolemmal voltage‐gated L‐type Ca2+ channels (LCCs) acts as a feed‐forward signal that triggers a large release of Ca2+ from the junctional sarcoplasmic reticulum (SR). This Ca2+ drives heart muscle contraction and pumping of blood in a process known as excitation–contraction coupling (ECC). Triggered and released Ca2+ also feed back to inactivate LCCs, attenuating the triggered Ca2+ signal once release has been achieved. The process of ECC consumes large amounts of ATP. It is now clear that in a process known as excitation–energetics coupling, Ca2+ signals exert beat‐to‐beat regulation of mitochondrial ATP production that closely couples energy production with demand. This occurs through transport of Ca2+ into mitochondria, where it regulates enzymes of the tricarboxylic acid cycle. In excitation–signaling coupling, Ca2+ activates a number of signaling pathways in a feed‐forward manner. Through effects on their target proteins, these interconnected pathways regulate Ca2+ signals in complex ways to control electrical excitability and contractility of heart muscle. In a process known as excitation–transcription coupling, Ca2+ acting primarily through signal transduction pathways also regulates the process of gene transcription. Because of these diverse and complex roles, experimentally based mechanistic computational models are proving to be very useful for understanding Ca2+ signaling in the cardiac myocyte. WIREs Syst Biol Med 2016, 8:37–67. doi: 10.1002/wsbm.1322 This article is categorized under: Biological Mechanisms > Cell Signaling Analytical and Computational Methods > Computational Methods Models of Systems Properties and Processes > Mechanistic Models
Basic states for a lobe of calmodulin (CaM) in complex with a Ca2+ channel. (Reprinted with permission from Ref . Copyright 2008). In state 1, apoCaM (yellow circle) is bound to the apoCaM site (round pocket). In state 2, apoCaM is transiently dissociated. In state 3, CaM binds two Ca2+ ions (black dots) to become Ca2+/CaM (yellow square), which can then bind the Ca2+/CaM effector site (square pocket), yielding Ca2+‐dependent inactivation (CDI; state 4). (Reprinted with permission from Ref . Copyright 2002 Cell Press.)
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The structural and molecular basis of cardiac excitation–contraction coupling. (Reprinted with permission from Ref . Copyright 2002 Nature Publishing Group.)
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Model of NFAT dynamics. (a) Simulated percent increase of green fluorescent protein (GFP)‐tagged nuclear dNFAT (ordinate) as a function of time (abscissa) in response to a sustained Ca2+ pulse with duration of 1.5 min, model (green) versus experiment (red). (b) Simulated percent increase of GFP‐tagged nuclear NFAT (ordinate) as a function of time (abscissa) in response to 30‐second Ca2+ pulses delivered at 1.5‐, 3‐, 6‐, and 15‐min intervals versus experimental results. (c) Simulated percent change in nuclear dNFAT as a function of heart rate, diastolic Ca2+ level, and nuclear IP3 level.
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The nuclear factor of activated T cell (NFAT) model reaction scheme: Under basal conditions, NFAT resides in a phosphorylated state (pNFAT) in the subsarcolemmal region of the cytoplasm. Upon elevation of Ca2+, calcineurin (CaN) is activated and can dephosphorylate NFAT, which enables its nuclear translocation via nuclear pore complex (NPC). In the nucleus, CaN competes with export kinases in maintaining elevated levels of dephosphorylated (dNFAT), which is in a transcriptionally active state and promotes transcription of prohypertrophic genes. CaM, calmodulin; CaN, calcineurin; IP3, inositol trisphosphate; NFAT, nuclear factor of activated T cells; NE, nuclear envelope; NPC, nuclear pore complex; RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca2+ATPase; SR, sarcoplasmic reticulum.
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Organization and molecular constituents of the nuclear Ca2+ compartment.
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Simulated results from a 1‐Hz action potential (AP) pacing protocol under different phosphorylation conditions of membrane potential (a) and diastolic type 2 ryanodine receptor (RyR2) flux (b). Every second, a current with −100 pA/pF amplitude and 0.5‐millisecond duration is applied to the membrane to stimulate APs. For each condition, 50 seconds of pacing is simulated and the results from all 50 APs are averaged and presented. (c) A simulated early after‐depolarization (EAD) under the same pacing protocol where the LCC phosphorylation rate has been increased by 10%.
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Spatial [Ca2+]i profiles during a Ca2+ spark predicted by the model of Walker et al. (a) Geometry of junctional sarcoplasmic reticulum (JSR) and t‐tubule. Green arrows and circle show orientations for distance, relative to the JSR and t‐tubule, for panels (a–c). (b) Positioning of 7 × 7 array of type 2 ryanodine receptors (RyR2s) and five L‐type Ca2+ channels (LCCs) in JSR. (c) Ca2+ concentration (μM) along the line labeled in (a). Position x = 0 is the center of the t‐tubule. Profiles are shown for the time of first RyR2 opening (0 millisecond), during peak subspace [Ca2+] (15 milliseconds), peak [Ca2+] on the back face of the JSR (18 milliseconds), and at the spark peak (21 milliseconds). The asymmetrical profile is due to local diffusion resistance imposed by the JSR in the +x direction. Inset shows the location of an intermyofibrillar mitochondrion spanning between adjacent t‐tubules; however, in these simulations this diffusion barrier is not present. (d) Profiles tangential to the back face of the JSR as labeled in (a). Slight asymmetry is due to uneven activation of the RyR2s during spark initiation. (e) Profiles tangential to the t‐tubule as labeled in (a), near the points of greatest subspace Ca2+ efflux, where [Ca2+]i reaches ~8–12 μM. (e) Ca2+ on the surface of a rectangular diffusion boundary approximating the shape of a mitochondrion at 10 milliseconds after first RyR2 opening.
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Organization of thin and thick filaments in the cardiac sarcomere. (Reprinted with permission from Ref . Copyright 2001 Cell Press.)
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