The Distinct Roles of Calmodulin and Calmodulin Kinase II in the Reversal of Run-Down of L-Type Ca2+ Channels in Guinea-Pig Ventricular Myocytes

Liang, Hao; Wang, Wuyang; Minobe, Etsuko; Han, Dong-Yun; Xu, Jianjun; Kameyama, Asako; Kameyama, Masaki

doi:10.1254/jphs.09094fp

Cited by 15 publications

(15 citation statements)

References 36 publications

(36 reference statements)

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“…Multiple factors have been identified to regulate the Cav1.2 channel through various mechanisms, including protein kinase phosphorylation and direct interaction with the channel. It is reported that the activity of the Cav1.2 channel is modulated by cAMP-dependent protein kinase (6, 16) and calmodulin (CaM) kinase II-mediated phosphorylation (14,15). Some studies indicate that CaM is directly tethered to the Cav1.2 channel and mediates the channel function (38,50,53).…”

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confidence: 99%

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Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Feng

Minobe

et al. 2014

American Journal of Physiology-Cell Physiology

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The present study is to investigate the mechanism by which ATP regulates Cav1.2 channel activity. Ventricular tissue was obtained from adult guinea pig hearts using collagenase. Ca(2+) channel activity was monitored using the patch-clamp technique. Proteins were purified using wheat germ agglutinin-Sepharose, and the concentration was determined using the Coomassie brilliant blue technique. ATP binding to the Cav1.2 channel was examined using the photoaffinity method. EDA-ATP-biotin maintains Ca(2+) channel activity in inside-out membrane patches. ATP directly bound to the Cav1.2 channel in a dose-dependent manner, and at least two molecules of ATP bound to one molecule of the Cav1.2 channel. Low levels of calmodulin (CaM) increased ATP binding to the Cav1.2 channel, but higher levels of CaM decreased ATP binding to the Cav1.2 channel. In addition, Ca(2+) was another regulator for ATP binding to the Cav1.2 channel. Furthermore, ATP bound to GST-fusion peptides of NH2-terminal region (amino acids 6-140) and proximal COOH-terminal region (amino acids 1,509-1,789) of the main subunit (α1C) of the Cav1.2 channel. Our data suggest that ATP might regulate Cav1.2 channel activity by directly binding to the Cav1.2 channel in a dose-dependent manner. In addition, the ATP-binding effect to the Cav1.2 channel was both CaM- and Ca(2+) dependent.

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“…kinase II-mediated phosphorylation (14,15). Some studies indicate that CaM is directly tethered to the Cav1.2 channel and mediates the channel function (38,50,53).…”

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confidence: 99%

Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Feng

Minobe

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Thus we mainly focused on NP o of I Na,P , which represented channel activity. As our previous studies showed that CaM and its mutants could modulate the activity of voltage-gated Ca 2ϩ channels (13, 15), we investigated whether CaM and its mutants could modulate VGSC activity according to our previously described method for measuring NP o of the channel (14,16).…”

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confidence: 99%

Low-Mg²⁺ treatment increases sensitivity of voltage-gated Na⁺ channels to Ca²⁺/calmodulin-mediated modulation in cultured hippocampal neurons

Guo

Zhou

Gao

et al. 2015

American Journal of Physiology-Cell Physiology

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Culture of hippocampal neurons in low-Mg(2+) medium (low-Mg(2+) neurons) results in induction of continuous seizure activity. However, the underlying mechanism of the contribution of low Mg(2+) to hyperexcitability of neurons has not been clarified. Our data, obtained using the patch-clamp technique, show that voltage-gated Na(+) channel (VGSC) activity, which is associated with a persistent, noninactivating Na(+) current (INa,P), was modulated by calmodulin (CaM) in a concentration-dependent manner in normal and low-Mg(2+) neurons, but the channel activity was more sensitive to Ca(2+)/CaM regulation in low-Mg(2+) than normal neurons. The increased sensitivity of VGSCs in low-Mg(2+) neurons was partially retained when CaM12 and CaM34, CaM mutants with disabled binding sites in the N or C lobe, were used but was diminished when CaM1234, a CaM mutant in which all four Ca(2+) sites are disabled, was used, indicating that functional Ca(2+)-binding sites from either lobe of CaM are required for modulation of VGSCs in low-Mg(2+) neurons. Furthermore, the number of neurons exhibiting colocalization of CaM with the VGSC subtypes NaV1.1, NaV1.2, and NaV1.3 was significantly higher in low- Mg(2+) than normal neurons, as shown by immunofluorescence. Our main finding is that low-Mg(2+) treatment increases sensitivity of VGSCs to Ca(2+)/CaM-mediated regulation. Our data reveal that CaM, as a core regulating factor, connects the functional roles of the three main intracellular ions, Na(+), Ca(2+), and Mg(2+), by modulating VGSCs and provides a possible explanation for the seizure discharge observed in low-Mg(2+) neurons.

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“…Phosphorylation of the Cav1.2 channels by CaMKII or PKA is reported to be required for channel activity [18,19]. Thus the possibility that the other nucleotides except ATP might have inhibited a protein kinase critical for maintaining channel activity cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Nucleotides maintain the activity of Cav1.2 channels in guinea-pig ventricular myocytes

Liu

Minobe

et al. 2015

Biochemical and Biophysical Research Communications

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The Distinct Roles of Calmodulin and Calmodulin Kinase II in the Reversal of Run-Down of L-Type Ca2+ Channels in Guinea-Pig Ventricular Myocytes

Cited by 15 publications

References 36 publications

Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Low-Mg²⁺ treatment increases sensitivity of voltage-gated Na⁺ channels to Ca²⁺/calmodulin-mediated modulation in cultured hippocampal neurons

Nucleotides maintain the activity of Cav1.2 channels in guinea-pig ventricular myocytes

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The Distinct Roles of Calmodulin and Calmodulin Kinase II in the Reversal of Run-Down of L-Type Ca2+ Channels in Guinea-Pig Ventricular Myocytes

Cited by 15 publications

References 36 publications

Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner

Low-Mg2+ treatment increases sensitivity of voltage-gated Na+ channels to Ca2+/calmodulin-mediated modulation in cultured hippocampal neurons

Nucleotides maintain the activity of Cav1.2 channels in guinea-pig ventricular myocytes

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Low-Mg²⁺ treatment increases sensitivity of voltage-gated Na⁺ channels to Ca²⁺/calmodulin-mediated modulation in cultured hippocampal neurons