Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes

AbstractRecent data on structure of dyads in cardiac myocytes indicate variable clustering of RyR calcium release channels. The question arises as to how geometric factors of RyR arrangement translate to their role in formation of calcium release events (CRE). Since this question is not experimentally testable in situ, we performed in silico experiments on a large set of calcium release site (CRS) models. The models covered the range of RyR spatial distributions observed in dyads, and included gating of RyRs with open probability dependent on Ca2+ and Mg2+ concentration. The RyR single-channel calcium current, varied in the range of previously reported values, was set constant in the course of CRE simulations. Other known features of dyads were omitted in the model formulation for clarity. CRE simulations initiated by a single random opening of one of the RyRs in a CRS produced spark-like responses with characteristics that varied with RyR vicinity, a newly defined parameter quantifying spatial distribution of RyRs in the CRSs, and with the RyR single-channel calcium current. The CRE characteristics followed the law of mass action with respect to a CRS state variable, defined as a weighed product of RyR vicinity and RyR single-channel calcium current. The results explained the structure-function relations among determinants of cardiac dyads on synergy principles and thus allowed to evolve the concept of CRS as a dynamic unit of cardiac dyad.

Download Full-text

Activation of calcium release assessed by calcium release-induced inactivation of calcium current in rat cardiac myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00272.2003 ◽

2004 ◽

Vol 286 (2) ◽

pp. C330-C341 ◽

Cited By ~ 28

Author(s):

Alexandra Zahradníková ◽

Zuzana Kubalová ◽

Jana Pavelková ◽

Sándor Györke ◽

Ivan Zahradník

Keyword(s):

Cardiac Myocytes ◽

Lipid Bilayers ◽

Calcium Current ◽

Calcium Release ◽

Flash Photolysis ◽

Ventricular Myocytes ◽

Calcium Influx ◽

Ryanodine Receptors ◽

Test Pulse ◽

Dyadic Space

In mammalian cardiac myocytes, calcium released into the dyadic space rapidly inactivates calcium current ( ICa). We used this Ca2+ release-dependent inactivation (RDI) of ICa as a local probe of sarcoplasmic reticulum Ca2+ release activation. In whole cell patch-clamped rat ventricular myocytes, Ca2+ entry induced by short prepulses from —50 mV to positive voltages caused suppression of peak ICa during a test pulse. The negative correlation between peak ICa suppression and ICa inactivation during the test pulse indicated that RDI evoked by the prepulse affected only calcium channels in those dyads in which calcium release was activated. Ca2+ ions injected during the prepulse and during the subsequent tail current suppressed peak ICa in the test pulse to a different extent. Quantitative analysis indicated that equal Ca2+ charge was 3.5 times less effective in inducing release when entering during the prepulse than when entering during the tail. Tail Ca2+ charge injected by the first voltage-dependent calcium channel (DHPR) openings was three times less effective than that injected by DHPR reopenings. These findings suggest that calcium release activation can be profoundly influenced by the recent history of L-type Ca2+ channel activity due to potentiation of ryanodine receptors (RyRs) by previous calcium influx. This conclusion was confirmed at the level of single RyRs in planar lipid bilayers: using flash photolysis of the calcium cage NP-EGTA to generate two sequential calcium stimuli, we showed that RyR activation in response to the second stimulus was four times higher than that in response to the first stimulus.

Download Full-text

In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes

The Journal of General Physiology ◽

10.1085/jgp.202012685 ◽

2021 ◽

Vol 153 (4) ◽

Author(s):

Bogdan I. Iaparov ◽

Ivan Zahradnik ◽

Alexander S. Moskvin ◽

Alexandra Zahradníková

Keyword(s):

Cardiac Myocytes ◽

In Silico ◽

Calcium Current ◽

Calcium Release ◽

Ryanodine Receptors ◽

Physiological Role ◽

Spatial Arrangement ◽

Large Set ◽

Calcium Sparks ◽

Open Probability

The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with the spatial distribution of RYRs in the CRS but did not consistently correlate with RYR number, surface density, or calcium current. However, it correlated with RYR coupling strength, defined as the weighted product of RYR vicinity and calcium current, so that CRE characteristics of all models followed the same state-response function. This finding revealed the synergy between structure and function of CRSs in shaping dyad function. Lastly, rearrangements of RYRs simulating hypothetical experiments on splitting and compaction of a dyad revealed an increased propensity to generate spontaneous sparks and an overall increase in calcium release in smaller and more compact dyads, thus underlying the importance and physiological role of RYR arrangement in cardiac myocytes.

Download Full-text

Calcium Waves and Closure of Potassium Channels in Response to GABA Stimulation in Hermissenda Type B Photoreceptors

Journal of Neurophysiology ◽

10.1152/jn.00867.2000 ◽

2002 ◽

Vol 87 (2) ◽

pp. 776-792 ◽

Cited By ~ 11

Author(s):

K. T. Blackwell

Keyword(s):

Calcium Current ◽

Calcium Concentration ◽

Calcium Release ◽

Input Resistance ◽

Receptor Activation ◽

Memory Storage ◽

Type B ◽

Kinase C ◽

Hyperpolarization Activated Current ◽

Receptor Channel

Classical conditioning of Hermissenda crassicornisrequires the paired presentation of a conditioned stimulus (light) and an unconditioned stimulus (turbulence). Light stimulation of photoreceptors leads to production of diacylglycerol, an activator of protein kinase C, and inositol triphosphate (IP3), which releases calcium from intracellular stores. Turbulence causes hair cells to release GABA onto the terminal branches of the type B photoreceptor. One prior study has shown that GABA stimulation produces a wave of calcium that propagates from the terminal branches to the soma and raises the possibility that two sources of calcium are required for memory storage. GABA stimulation also causes an inhibitory postsynaptic potential (IPSP) followed by a late depolarization and increase in input resistance, whose cause has not been identified. A model was developed of the effect of GABA stimulation on the Hermissenda type B photoreceptor to evaluate the currents underlying the late depolarization and to evaluate whether a calcium wave could propagate from the terminal branches to the soma. The model included GABAA, GABAB, and calcium-sensitive potassium leak channels; calcium dynamics including release of calcium from intracellular stores; and the biochemical reactions leading from GABAB receptor activation to IP3 production. Simulations show that it is possible for a wave of calcium to propagate from the terminal branches to the soma. The wave is initiated by IP3-induced calcium release but propagation requires release through the ryanodine receptor channel where IP3 concentration is small. Wave speed is proportional to peak calcium concentration at the crest of the wave, with a minimum speed of 9 μm/s in the absence of IP3. Propagation ceases when peak concentration drops below 1.2 μM; this occurs if the rate of calcium pumping into the endoplasmic reticulum is too large. Simulations also show that both a late depolarization and an increase in input resistance occur after GABA stimulation. The duration of the late depolarization corresponds to the duration of potassium leak channel closure. Neither the late depolarization nor the increase in input resistance are observed when a transient calcium current and a hyperpolarization-activated current are added to the model as replacement for closure of potassium leak channels. Thus the late depolarization and input resistance elevation can be explained by a closure of calcium-sensitive leak potassium currents but cannot be explained by a transient calcium current and a hyperpolarization-activated current.

Download Full-text

Construction of Calcium Release Sites in Cardiac Myocytes

Frontiers in Physiology ◽

10.3389/fphys.2012.00322 ◽

2012 ◽

Vol 3 ◽

Cited By ~ 7

Author(s):

Alexandra Zahradníková ◽

Ivan Zahradník

Keyword(s):

Cardiac Myocytes ◽

Calcium Release

Download Full-text

Antibody-mediated enhancement of calcium permeability in cardiac myocytes.

Journal of Experimental Medicine ◽

10.1084/jem.168.6.2105 ◽

1988 ◽

Vol 168 (6) ◽

pp. 2105-2119 ◽

Cited By ~ 95

Author(s):

H P Schultheiss ◽

U Kühl ◽

I Janda ◽

B Melzner ◽

G Ulrich ◽

...

Keyword(s):

Calcium Channel ◽

Cardiac Myocytes ◽

Calcium Current ◽

Antigenic Determinant ◽

Mitochondrial Membrane ◽

Cytotoxic Effect ◽

Calcium Overload ◽

Channel Blockers ◽

Inner Mitochondrial Membrane ◽

Calcium Permeability

Our study shows that antibodies, specific to the ADP/ATP carrier of the inner mitochondrial membrane, crossreact with the cell surface of cardiac myocytes, where the calcium channel seems to be the antigenic determinant. The antibodies enhanced the calcium current and suppressed its inactivation. Affinity-purified antibodies (IgG) exhibit an acute cytotoxic effect, which required extracellular calcium and was prevented by calcium channel blockers. Our findings suggest that antibody-mediated cytotoxicity results secondary to calcium overload caused by enhanced cellular calcium permeability, requiring no complement-dependent process.

Download Full-text