Limits...
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

Inactivation of cardiac Ca2+ channel. (A) Normalized ICa, IBa, and INS elicited by a square voltage pulse at room temperature to 0 mV (except INS at −30 mV to obtain comparable activation state). ICa was recorded under both perforated patch (where normal SR Ca2+ release and Ca2+ transients occur) and ruptured patch conditions with cells dialyzed with 10 mM EGTA (to prevent global Ca2+ transients). IBa was also recorded with ruptured patch (with 10 mM EGTA in the pipette). Extracellular [Ca2+] and [Ba2+] were both 2 mM and INS was measured in divalent-free conditions (10 mM EDTA inside and out) with extracellular [Na+] at 20 mM and intracellular [Na+] at 10 mM. Peak currents were 1370, 808, 780, and 5200 pA and were attained at 5, 7, 10, and 14 ms for ICa (perforated), ICa (ruptured), IBa and INS respectively, with t1/2 of current decline of 17, 37, 161, and > 500 ms respectively. (B) Amplitude of INS and ICa through LTCC (at −10 mV) after 500 ms pulses to the indicated Em in guinea-pig ventricular myocytes (modified from Bers, 2001 with permission, data from Hadley and Hume, 1987).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4060732&req=5

Figure 1: Inactivation of cardiac Ca2+ channel. (A) Normalized ICa, IBa, and INS elicited by a square voltage pulse at room temperature to 0 mV (except INS at −30 mV to obtain comparable activation state). ICa was recorded under both perforated patch (where normal SR Ca2+ release and Ca2+ transients occur) and ruptured patch conditions with cells dialyzed with 10 mM EGTA (to prevent global Ca2+ transients). IBa was also recorded with ruptured patch (with 10 mM EGTA in the pipette). Extracellular [Ca2+] and [Ba2+] were both 2 mM and INS was measured in divalent-free conditions (10 mM EDTA inside and out) with extracellular [Na+] at 20 mM and intracellular [Na+] at 10 mM. Peak currents were 1370, 808, 780, and 5200 pA and were attained at 5, 7, 10, and 14 ms for ICa (perforated), ICa (ruptured), IBa and INS respectively, with t1/2 of current decline of 17, 37, 161, and > 500 ms respectively. (B) Amplitude of INS and ICa through LTCC (at −10 mV) after 500 ms pulses to the indicated Em in guinea-pig ventricular myocytes (modified from Bers, 2001 with permission, data from Hadley and Hume, 1987).

Mentions: Figure 1A shows ICa inactivation kinetics in a rabbit ventricular myocyte under different Ca2+ conditions. The time to half inactivation (t1/2) increases from 17 to 37 ms when normal Ca2+ transients are abolished (e.g., by buffering the intracellular Ca2+ with 10 mM EGTA). Note that EGTA is a relatively slow buffer and cannot abolish very local [Ca2+] elevation around the mouth of the channel (although in this case SR Ca2+ release is prevented). In absence of extracellular Ca2+, LTCC are permeable to Ba2+, and this current (IBa) has been often studied to differentiate VDI and CDI (Lee et al., 1985; Peterson et al., 2000; Cens et al., 2006), despite a modest ability of Ba2+ to induce inactivation (Ferreira et al., 1997). When Ba2+ is the charge carrier (and intracellular Ca2+ is buffered), IBa inactivation is further slowed (t1/2 = 161 ms).


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

Bers DM, Morotti S - Front Pharmacol (2014)

Inactivation of cardiac Ca2+ channel. (A) Normalized ICa, IBa, and INS elicited by a square voltage pulse at room temperature to 0 mV (except INS at −30 mV to obtain comparable activation state). ICa was recorded under both perforated patch (where normal SR Ca2+ release and Ca2+ transients occur) and ruptured patch conditions with cells dialyzed with 10 mM EGTA (to prevent global Ca2+ transients). IBa was also recorded with ruptured patch (with 10 mM EGTA in the pipette). Extracellular [Ca2+] and [Ba2+] were both 2 mM and INS was measured in divalent-free conditions (10 mM EDTA inside and out) with extracellular [Na+] at 20 mM and intracellular [Na+] at 10 mM. Peak currents were 1370, 808, 780, and 5200 pA and were attained at 5, 7, 10, and 14 ms for ICa (perforated), ICa (ruptured), IBa and INS respectively, with t1/2 of current decline of 17, 37, 161, and > 500 ms respectively. (B) Amplitude of INS and ICa through LTCC (at −10 mV) after 500 ms pulses to the indicated Em in guinea-pig ventricular myocytes (modified from Bers, 2001 with permission, data from Hadley and Hume, 1987).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Inactivation of cardiac Ca2+ channel. (A) Normalized ICa, IBa, and INS elicited by a square voltage pulse at room temperature to 0 mV (except INS at −30 mV to obtain comparable activation state). ICa was recorded under both perforated patch (where normal SR Ca2+ release and Ca2+ transients occur) and ruptured patch conditions with cells dialyzed with 10 mM EGTA (to prevent global Ca2+ transients). IBa was also recorded with ruptured patch (with 10 mM EGTA in the pipette). Extracellular [Ca2+] and [Ba2+] were both 2 mM and INS was measured in divalent-free conditions (10 mM EDTA inside and out) with extracellular [Na+] at 20 mM and intracellular [Na+] at 10 mM. Peak currents were 1370, 808, 780, and 5200 pA and were attained at 5, 7, 10, and 14 ms for ICa (perforated), ICa (ruptured), IBa and INS respectively, with t1/2 of current decline of 17, 37, 161, and > 500 ms respectively. (B) Amplitude of INS and ICa through LTCC (at −10 mV) after 500 ms pulses to the indicated Em in guinea-pig ventricular myocytes (modified from Bers, 2001 with permission, data from Hadley and Hume, 1987).
Mentions: Figure 1A shows ICa inactivation kinetics in a rabbit ventricular myocyte under different Ca2+ conditions. The time to half inactivation (t1/2) increases from 17 to 37 ms when normal Ca2+ transients are abolished (e.g., by buffering the intracellular Ca2+ with 10 mM EGTA). Note that EGTA is a relatively slow buffer and cannot abolish very local [Ca2+] elevation around the mouth of the channel (although in this case SR Ca2+ release is prevented). In absence of extracellular Ca2+, LTCC are permeable to Ba2+, and this current (IBa) has been often studied to differentiate VDI and CDI (Lee et al., 1985; Peterson et al., 2000; Cens et al., 2006), despite a modest ability of Ba2+ to induce inactivation (Ferreira et al., 1997). When Ba2+ is the charge carrier (and intracellular Ca2+ is buffered), IBa inactivation is further slowed (t1/2 = 161 ms).

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