Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart
Section snippets
Sources of activator Ca2+ for contraction in the heart
To activate contraction in cardiac myocytes, addition of approximately 100 μmol L−1 Ca2+ to the cytosol during the action potential is required. Whilst there are species differences in the absolute fraction, the vast majority of the total Ca2+ requirement is met by Ca2+ release from the intracellular store, the sarcoplasmic reticulum (SR). There have been two proposed mechanisms that initiate Ca2+ release from the SR during the action potential: (i) Ca2+ induced Ca2+ release (CICR) in response to
Controlling SR Ca2+ content: distinct roles for the L-type Ca2+ channel and Na+–Ca2+ exchanger
Whilst Ca2+ entry across the sarcolemma is required to initiate cardiac excitation contraction coupling, the majority of the ∼100 μmol L−1 Ca2+ required to produce contraction in the heart is released from the intracellular Ca2+ store, the SR. This section will investigate the mechanisms that are responsible for firstly filling the Ca2+ depleted SR and then tightly controlling the amount of Ca2+ stored within the SR.
Rapid inotropy without a need to change SR Ca2+ content
There is an obvious requirement for the inotropic state of the heart to be altered to meet the various demands of the body e.g. exercise or the flight-fight response. Given the steep (approximately cubic) dependence of systolic [Ca2+]i on SR Ca2+ content [10], [23] one might at first suggest increasing SR Ca2+ content as a means to increase contractility. Indeed, some of the earliest experiments in this field demonstrated that changing the extracellular Ca2+ concentration and therefore Ca2+
Role of altered SR Ca2+ release in ageing and heart disease
The above discussion has shown how sarcolemmal Ca2+ fluxes are pivotal to controlling SR Ca2+ content. We will now consider how these various control points become disrupted and lead to alterations in cardiac excitation contraction coupling in two patho-physiological models; (i) ageing and (ii) heart disease.
Diastolic Ca2+ leak, arrhythmias and novel management strategies
As discussed above, changes in the balance between SR and sarcolemmal mechanisms for removing Ca2+ from the cytoplasm have profound effects on systolic [Ca2+]i and thus cardiac function. Such analysis accounts for nearly all of the fall of SR Ca2+ content in a model of heart disease. However, in addition to the above effects on Ca2+ removal mechanisms, it has also been suggested that an increased diastolic leak of Ca2+ from the SR contributes both to a decrease of SR Ca2+ content and an
Conclusions
We have described some of the factors that are responsible for initiating and subsequently controlling the amplitude of the systolic Ca2+ transient in cardiac muscle. We conclude: (i) that there is an absolute requirement for sarcolemmal Ca2+ entry during the action potential to trigger Ca2+ release from the intracellular Ca2+ store in cardiac muscle; (ii) a simple negative feedback mechanism exists to control the amount of Ca2+ that is stored in the SR and thus the amplitude of the systolic Ca
Acknowledgements
The work described in this review (excepting Fig. 1A and B) was supported by grants from The British Heart Foundation and Sonderforschungsbereich 598, Germany.
References (49)
- et al.
No role for a voltage-sensitive release mechanism in cardiac muscle
J. Mol. Cell. Cardiol.
(2003) - et al.
Store-operated Ca2+ entry uncoupled with ryanodine receptor and junctional membrane complex in heart muscle cells
Cell Calcium
(2002) - et al.
A mechanism distinct from the L-type Ca current or Na–Ca exchange contributes to Ca entry in rat ventricular myocytes
Cell Calcium
(2006) Recent developments in non-excitable cell calcium entry
Cell Calcium
(2001)- et al.
Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium
J. Mol. Cell. Cardiol.
(2004) - et al.
PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts
Cell
(2000) - et al.
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death
Cell
(2003) - et al.
Regulation of calcium transport by the ATPase-phospholamban system
J. Mol. Cell. Cardiol.
(1983) - et al.
Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells
J. Physiol.
(1975) - et al.
Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum
Science
(1990)
Contractions in guinea-pig ventricular myocytes triggered by a calcium-release mechanism separate from Na+ and L-currents
J. Physiol.
Low efficiency of Ca2+ entry through the Na+–Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum
Circ. Res.
The control of tonic tension by membrane potential and intracellular sodium activity in the sheep cardiac Purkinje fibre
J. Physiol.
Properties of “creep currents” in single frog atrial cells
J. Gen. Physiol.
Sodium–calcium exchange in heart: membrane currents and changes in [Ca2+]i
Science
Tension-voltage relations of single myocytes reflect Ca release triggered by Na/Ca exchange at 35 °C but not at 23 °C
Am. J. Physiol.
Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes
Am. J. Physiol.
The voltage-sensitive release mechanism of excitation contraction coupling in rabbit cardiac muscle is explained by calcium-induced calcium release
J. Gen. Physiol.
Effects of mechanical stretch on membrane currents of single ventricular myocytes of guinea-pig heart
Jpn. J. Physiol.
Barium- and calcium-permeable channels open at negative membrane potentials in rat ventricular myocytes
J. Membr. Biol.
Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca(2+) channel mediating angiotensin II-induced myocardial apoptosis
Mol. Cell. Biochem.
An estimate of the calcium content of the sarcoplasmic reticulum in rat ventricular myocytes
Pflügers Archiv.
Enhanced calcium current and decreased calcium efflux restore sarcoplasmic reticulum Ca content following depletion
Circ. Res.
Depletion of Ca2+ from the sarcoplasmic reticulum of cardiac muscle prompts phosphorylation of phospholamban to stimulate store refilling
Proc. Natl. Acad. Sci. U.S.A.
Cited by (70)
A hydroalcoholic extract of Senecio nutans SCh. Bip (Asteraceae); its effects on cardiac function and chemical characterization
2023, Journal of EthnopharmacologyCitation Excerpt :S. nutans decreases the [Ca2+]i transient amplitude, accounting for reduced systolic shortening (Bers, 2002). The amplitude of the [Ca2+]i transient is proportional to the third power of the SR Ca2+ content (Dibb et al., 2007). S. nutans reduced SR Ca2+ content to 76% of control.
Improved Ca<sup>2+</sup> release synchrony following selective modification of I<inf>tof</inf> and phase 1 repolarization in normal and failing ventricular myocytes
2022, Journal of Molecular and Cellular CardiologyCitation Excerpt :Despite there being no difference in Ca2+ transient amplitude at steady-state with the +Itof,DyC AP, there was maintained improvement in Ca2+ release synchrony at steady-state (Fig. 5B,C), together with a slightly shorter Ca2+ transient duration (control 380 ± 31 ms; +Itof,DyC 372 ± 21 ms; P < 0.05, n/N = 8/3). At the end of the pacing sequence the control AP was re-applied and this resulted in an immediate drop in Ca2+ transient amplitude (arrow in Fig. 5A), as might be expected if the increased SR release seen immediately upon adding Ito,f,DyC depleted the SR Ca2+ store without an increase in Ca2+ influx via ICa [34]. Ca2+ influx via ICa is sensitive to the magnitude of local SR release so that increasing release synchrony can reduce net Ca2+ influx due to local Ca2+ − dependent inactivation of Ca2+ channels [35].
VDAC2 as a novel target for heart failure: Ca<sup>2+</sup> at the sarcomere, mitochondria and SR
2022, Cell CalciumCitation Excerpt :In addition to this energy balance for ATP, contractility also requires the transient flux of cytosolic Ca2+ on a beat-to-beat basis in order to activate key Ca2+ dependent steps of actin-myosin crossbridge shortening [5]. Indeed, the height of the Ca2+ transient and ATP availability are key determinants of the force of contraction of individual cardiomyocytes which involves communication between the sarcomere, sarcoplasmic reticulum (SR) and mitochondria [6,7]. Ca2+ transients in cardiomyocytes are triggered by the opening of the L-type Ca2+ channels in the T-tubule membrane and then the emptying of the ryanodine receptor (RYR2) Ca2+ stores by Ca2+ induced Ca2+ release [8,9].
Do human sinoatrial node cells have t-tubules?
2021, Translational Research in AnatomyDipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure
2017, Biochemical PharmacologyRyanodine Receptor Channelopathies in Skeletal and Cardiac Muscle
2016, Ion Channels in Health and Disease