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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

CaMKII-dependent regulation of ICa. Superimposed ICa traces from the first (I1) and tenth (I10) voltage-clamp pulse from −90 to 0 mV at 2 Hz in a single rabbit ventricular myocyte obtained in control condition (A) or after 10 min equilibration with the CaMKII inhibitor KN-62 (1 μM) (B); I1 and I10 obtained in the two conditions are respectively shown (superimposed) in panels (C,D) (modified from Yuan and Bers, 1994 with permission). (E) A single LTCC current (channel openings are seen as downward deflections from baseline) is elicited by repetitive depolarizing voltage-clamp steps (from −70 to 0 mV) and reveals infrequent, brief openings under basal conditions (upper panel). CaMKII (bottom) causes frequent and prolonged LTCC openings compared with baseline. Panel (F) shows that the probability of LTCC opening during a depolarizing voltage-clamp step is dramatically increased upon addition of CaMKII, compared with basal conditions (modified from Anderson, 2004 with permission, data from Dzhura et al., 2002).
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Figure 4: CaMKII-dependent regulation of ICa. Superimposed ICa traces from the first (I1) and tenth (I10) voltage-clamp pulse from −90 to 0 mV at 2 Hz in a single rabbit ventricular myocyte obtained in control condition (A) or after 10 min equilibration with the CaMKII inhibitor KN-62 (1 μM) (B); I1 and I10 obtained in the two conditions are respectively shown (superimposed) in panels (C,D) (modified from Yuan and Bers, 1994 with permission). (E) A single LTCC current (channel openings are seen as downward deflections from baseline) is elicited by repetitive depolarizing voltage-clamp steps (from −70 to 0 mV) and reveals infrequent, brief openings under basal conditions (upper panel). CaMKII (bottom) causes frequent and prolonged LTCC openings compared with baseline. Panel (F) shows that the probability of LTCC opening during a depolarizing voltage-clamp step is dramatically increased upon addition of CaMKII, compared with basal conditions (modified from Anderson, 2004 with permission, data from Dzhura et al., 2002).

Mentions: About 20 years ago three groups independently demonstrated that Ca2+-dependent ICa facilitation is mediated by CaMKII-dependent phosphorylation of LTCC (Anderson et al., 1994; Xiao et al., 1994; Yuan and Bers, 1994). Xiao et al. (1994) also observed that sarcolemmal CaMKII activation correlates qualitatively with the changes in ICa. All three studies reported that pharmacological inhibition of CaMKII abolishes CDF in mammalian cardiomyocytes (Figures 4A–D). Anderson's group extended this work by characterizing the CaMKII-dependent effect on single channel ICa recorded in excised inside-out patches (Dzhura et al., 2000). They showed that addition of activated CaMKII to the cytoplasmic side of the sarcolemma results in phosphorylation of the LTCC complex, inducing high-activity (mode 2) gating that is characterized by long frequent openings (Figures 4E,F), consistently with the macroscopic effect of CDF.


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

Bers DM, Morotti S - Front Pharmacol (2014)

CaMKII-dependent regulation of ICa. Superimposed ICa traces from the first (I1) and tenth (I10) voltage-clamp pulse from −90 to 0 mV at 2 Hz in a single rabbit ventricular myocyte obtained in control condition (A) or after 10 min equilibration with the CaMKII inhibitor KN-62 (1 μM) (B); I1 and I10 obtained in the two conditions are respectively shown (superimposed) in panels (C,D) (modified from Yuan and Bers, 1994 with permission). (E) A single LTCC current (channel openings are seen as downward deflections from baseline) is elicited by repetitive depolarizing voltage-clamp steps (from −70 to 0 mV) and reveals infrequent, brief openings under basal conditions (upper panel). CaMKII (bottom) causes frequent and prolonged LTCC openings compared with baseline. Panel (F) shows that the probability of LTCC opening during a depolarizing voltage-clamp step is dramatically increased upon addition of CaMKII, compared with basal conditions (modified from Anderson, 2004 with permission, data from Dzhura et al., 2002).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: CaMKII-dependent regulation of ICa. Superimposed ICa traces from the first (I1) and tenth (I10) voltage-clamp pulse from −90 to 0 mV at 2 Hz in a single rabbit ventricular myocyte obtained in control condition (A) or after 10 min equilibration with the CaMKII inhibitor KN-62 (1 μM) (B); I1 and I10 obtained in the two conditions are respectively shown (superimposed) in panels (C,D) (modified from Yuan and Bers, 1994 with permission). (E) A single LTCC current (channel openings are seen as downward deflections from baseline) is elicited by repetitive depolarizing voltage-clamp steps (from −70 to 0 mV) and reveals infrequent, brief openings under basal conditions (upper panel). CaMKII (bottom) causes frequent and prolonged LTCC openings compared with baseline. Panel (F) shows that the probability of LTCC opening during a depolarizing voltage-clamp step is dramatically increased upon addition of CaMKII, compared with basal conditions (modified from Anderson, 2004 with permission, data from Dzhura et al., 2002).
Mentions: About 20 years ago three groups independently demonstrated that Ca2+-dependent ICa facilitation is mediated by CaMKII-dependent phosphorylation of LTCC (Anderson et al., 1994; Xiao et al., 1994; Yuan and Bers, 1994). Xiao et al. (1994) also observed that sarcolemmal CaMKII activation correlates qualitatively with the changes in ICa. All three studies reported that pharmacological inhibition of CaMKII abolishes CDF in mammalian cardiomyocytes (Figures 4A–D). Anderson's group extended this work by characterizing the CaMKII-dependent effect on single channel ICa recorded in excised inside-out patches (Dzhura et al., 2000). They showed that addition of activated CaMKII to the cytoplasmic side of the sarcolemma results in phosphorylation of the LTCC complex, inducing high-activity (mode 2) gating that is characterized by long frequent openings (Figures 4E,F), consistently with the macroscopic effect of CDF.

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