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Ca(2+) current facilitation is CaMKII-dependent and has arrhythmogenic consequences.

Bers DM, Morotti S - Front Pharmacol (2014)

Bottom Line: The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high.CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation.CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Davis Davis, CA, USA.

ABSTRACT
The cardiac voltage gated Ca(2+) current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca(2+)-dependent inactivation (CDI), Ca(2+)-dependent facilitation (CDF) and how calmodulin (CaM) and Ca(2+)-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca(2+) current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca(2+) channel, such that Ca(2+) influx and Ca(2+) released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.

No MeSH data available.


Related in: MedlinePlus

ICa inactivation during the AP. (A) Rabbit ventricular myocytes (at 25°C) were voltage-clamped with either a square voltage step or an AP waveform (measured from 5 other cells under physiological conditions). All other currents were blocked, e.g., by replacement of K+ with Cs+ and Na+ with TEA (inside and out) and cells were dialyzed with 10 mM EGTA to prevent Ca2+ transients (data from Yuan et al., 1996, modified from Bers, 2001 with permission). (B) After SR Ca2+ was depleted by a brief caffeine-application (with Na+), a series of AP-clamps were given, and contraction and ICa recovered to steady state over 10 sequential pulses at 25°C in rabbit ventricular myocyte (modified from Bers, 2001 with permission, data from Puglisi et al., 1999).
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Figure 2: ICa inactivation during the AP. (A) Rabbit ventricular myocytes (at 25°C) were voltage-clamped with either a square voltage step or an AP waveform (measured from 5 other cells under physiological conditions). All other currents were blocked, e.g., by replacement of K+ with Cs+ and Na+ with TEA (inside and out) and cells were dialyzed with 10 mM EGTA to prevent Ca2+ transients (data from Yuan et al., 1996, modified from Bers, 2001 with permission). (B) After SR Ca2+ was depleted by a brief caffeine-application (with Na+), a series of AP-clamps were given, and contraction and ICa recovered to steady state over 10 sequential pulses at 25°C in rabbit ventricular myocyte (modified from Bers, 2001 with permission, data from Puglisi et al., 1999).

Mentions: The time course of ICa during the AP is significantly different compared to that seen during a square voltage pulse [Figure 2A, rabbit ventricular myocyte, 25°C, with 10 mM EGTA to prevent Ca2+ transients (Yuan et al., 1996)]. Peak ICa during the AP is lower and occurs later than during a square pulse, with larger ICa late in the AP. The later ICa peak is because at the AP peak (+50 mV) Ca2+ channels activate rapidly, but the driving force for Ca2+ (Em–ECa) is initially low, because Em is close to the reversal potential for ICa (ECa ~ +60 mV). As Em repolarizes, the driving force increases faster than channel inactivation, producing a larger current at later times during the AP (Sah et al., 2002). Sipido et al. (1995) first investigated how Ca2+ released from the SR modulates ICa performing “classic” voltage-clamp experiments, and observed that CDI increases as SR Ca2+ release gets larger. Our group confirmed this observation in a more “physiological” condition, as shown in Figure 2B, where repeated AP-clamps are performed as the SR Ca2+ stores are reloaded, such that contractions get progressively larger (beat 1–10; Puglisi et al., 1999). One can see the contribution of SR Ca2+ release to CDI as the Ca2+ transients and contractions get larger. Integration of the Ca2+ influx via ICa during these ten pulses (which approach the steady state) shows that the ICa-dependent influx decreases from 12 to 6 μmol/L cytosol, indicating that ICa inactivation due to SR Ca2+ release decreases net Ca2+ influx by about 50%. These experiments were done at both 25 and 35°C. At 35°C peak ICa occurs earlier and is higher, but also inactivates faster and the AP duration is also shorter. The net result is that there is very little difference between these temperatures for the integral of Ca2+ influx during the AP (with SR Ca2+ release fully functional).


Ca(2+) current facilitation is CaMKII-dependent and has arrhythmogenic consequences.

Bers DM, Morotti S - Front Pharmacol (2014)

ICa inactivation during the AP. (A) Rabbit ventricular myocytes (at 25°C) were voltage-clamped with either a square voltage step or an AP waveform (measured from 5 other cells under physiological conditions). All other currents were blocked, e.g., by replacement of K+ with Cs+ and Na+ with TEA (inside and out) and cells were dialyzed with 10 mM EGTA to prevent Ca2+ transients (data from Yuan et al., 1996, modified from Bers, 2001 with permission). (B) After SR Ca2+ was depleted by a brief caffeine-application (with Na+), a series of AP-clamps were given, and contraction and ICa recovered to steady state over 10 sequential pulses at 25°C in rabbit ventricular myocyte (modified from Bers, 2001 with permission, data from Puglisi et al., 1999).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4060732&req=5

Figure 2: ICa inactivation during the AP. (A) Rabbit ventricular myocytes (at 25°C) were voltage-clamped with either a square voltage step or an AP waveform (measured from 5 other cells under physiological conditions). All other currents were blocked, e.g., by replacement of K+ with Cs+ and Na+ with TEA (inside and out) and cells were dialyzed with 10 mM EGTA to prevent Ca2+ transients (data from Yuan et al., 1996, modified from Bers, 2001 with permission). (B) After SR Ca2+ was depleted by a brief caffeine-application (with Na+), a series of AP-clamps were given, and contraction and ICa recovered to steady state over 10 sequential pulses at 25°C in rabbit ventricular myocyte (modified from Bers, 2001 with permission, data from Puglisi et al., 1999).
Mentions: The time course of ICa during the AP is significantly different compared to that seen during a square voltage pulse [Figure 2A, rabbit ventricular myocyte, 25°C, with 10 mM EGTA to prevent Ca2+ transients (Yuan et al., 1996)]. Peak ICa during the AP is lower and occurs later than during a square pulse, with larger ICa late in the AP. The later ICa peak is because at the AP peak (+50 mV) Ca2+ channels activate rapidly, but the driving force for Ca2+ (Em–ECa) is initially low, because Em is close to the reversal potential for ICa (ECa ~ +60 mV). As Em repolarizes, the driving force increases faster than channel inactivation, producing a larger current at later times during the AP (Sah et al., 2002). Sipido et al. (1995) first investigated how Ca2+ released from the SR modulates ICa performing “classic” voltage-clamp experiments, and observed that CDI increases as SR Ca2+ release gets larger. Our group confirmed this observation in a more “physiological” condition, as shown in Figure 2B, where repeated AP-clamps are performed as the SR Ca2+ stores are reloaded, such that contractions get progressively larger (beat 1–10; Puglisi et al., 1999). One can see the contribution of SR Ca2+ release to CDI as the Ca2+ transients and contractions get larger. Integration of the Ca2+ influx via ICa during these ten pulses (which approach the steady state) shows that the ICa-dependent influx decreases from 12 to 6 μmol/L cytosol, indicating that ICa inactivation due to SR Ca2+ release decreases net Ca2+ influx by about 50%. These experiments were done at both 25 and 35°C. At 35°C peak ICa occurs earlier and is higher, but also inactivates faster and the AP duration is also shorter. The net result is that there is very little difference between these temperatures for the integral of Ca2+ influx during the AP (with SR Ca2+ release fully functional).

Bottom Line: The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high.CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation.CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California Davis Davis, CA, USA.

ABSTRACT
The cardiac voltage gated Ca(2+) current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca(2+)-dependent inactivation (CDI), Ca(2+)-dependent facilitation (CDF) and how calmodulin (CaM) and Ca(2+)-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca(2+) current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca(2+) channel, such that Ca(2+) influx and Ca(2+) released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.

No MeSH data available.


Related in: MedlinePlus