Calmodulin kinase is functionally targeted to the action potential plateau for regulation of L-type Ca2+ current in rabbit cardiomyocytes

Yuejin Wu, John T. Kimbrough, Roger J. Colbran, Mark Anderson

Research output: Contribution to journalArticle

Abstract

L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Cai2+) for feedback regulation of ICa-L-. Cai2+ bound to calmodulin (Ca2+-CaM) can inhibit ICa-L, while Ca2+-CaM can also activate Ca2+-CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is not known whether ICa-L or the SR is the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+-CaM and CaMK, and the C terminus undergoes voltage-dependent steric changes, suggesting that Cai2+ control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+-CaM and CaMK to ICa-L and SR Cai2+ release during voltage clamp conditions modelled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa-L after brief positive conditioning pulses, whereas Ca2+-CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+-CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Cai2+ from ICa-L was sufficient for Ca2+-CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+-CaM and CaMK signalling.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalJournal of Physiology
Volume554
Issue number1
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinases
Sarcoplasmic Reticulum
Cardiac Myocytes
Action Potentials
Rabbits
Calmodulin
Membrane Potentials
Protein Kinases
Cell Membrane

ASJC Scopus subject areas

  • Physiology

Cite this

Calmodulin kinase is functionally targeted to the action potential plateau for regulation of L-type Ca2+ current in rabbit cardiomyocytes. / Wu, Yuejin; Kimbrough, John T.; Colbran, Roger J.; Anderson, Mark.

In: Journal of Physiology, Vol. 554, No. 1, 01.01.2004, p. 145-155.

Research output: Contribution to journalArticle

@article{389f23d656334efba163ed3d5d374ff5,
title = "Calmodulin kinase is functionally targeted to the action potential plateau for regulation of L-type Ca2+ current in rabbit cardiomyocytes",
abstract = "L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Cai2+) for feedback regulation of ICa-L-. Cai2+ bound to calmodulin (Ca2+-CaM) can inhibit ICa-L, while Ca2+-CaM can also activate Ca2+-CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is not known whether ICa-L or the SR is the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+-CaM and CaMK, and the C terminus undergoes voltage-dependent steric changes, suggesting that Cai2+ control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+-CaM and CaMK to ICa-L and SR Cai2+ release during voltage clamp conditions modelled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa-L after brief positive conditioning pulses, whereas Ca2+-CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+-CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Cai2+ from ICa-L was sufficient for Ca2+-CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+-CaM and CaMK signalling.",
author = "Yuejin Wu and Kimbrough, {John T.} and Colbran, {Roger J.} and Mark Anderson",
year = "2004",
month = "1",
day = "1",
doi = "10.1113/jphysiol.2003.053314",
language = "English (US)",
volume = "554",
pages = "145--155",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Calmodulin kinase is functionally targeted to the action potential plateau for regulation of L-type Ca2+ current in rabbit cardiomyocytes

AU - Wu, Yuejin

AU - Kimbrough, John T.

AU - Colbran, Roger J.

AU - Anderson, Mark

PY - 2004/1/1

Y1 - 2004/1/1

N2 - L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Cai2+) for feedback regulation of ICa-L-. Cai2+ bound to calmodulin (Ca2+-CaM) can inhibit ICa-L, while Ca2+-CaM can also activate Ca2+-CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is not known whether ICa-L or the SR is the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+-CaM and CaMK, and the C terminus undergoes voltage-dependent steric changes, suggesting that Cai2+ control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+-CaM and CaMK to ICa-L and SR Cai2+ release during voltage clamp conditions modelled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa-L after brief positive conditioning pulses, whereas Ca2+-CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+-CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Cai2+ from ICa-L was sufficient for Ca2+-CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+-CaM and CaMK signalling.

AB - L-type Ca2+ current (ICa-L) triggers Ca2+ release from the sarcoplasmic reticulum (SR) and both SR and ICa-L are potential sources of intracellular Ca2+ (Cai2+) for feedback regulation of ICa-L-. Cai2+ bound to calmodulin (Ca2+-CaM) can inhibit ICa-L, while Ca2+-CaM can also activate Ca2+-CaM-dependent protein kinase II (CaMK) to increase ICa. However, it is not known whether ICa-L or the SR is the primary source of Ca2+ for ICa-L regulation. The L-type Ca2+ channel C terminus is implicated as a critical transduction element for ICa-L responses to Ca2+-CaM and CaMK, and the C terminus undergoes voltage-dependent steric changes, suggesting that Cai2+ control of ICa-L may also be regulated by cell membrane potential. We developed conditions to separately test the relationship of Ca2+-CaM and CaMK to ICa-L and SR Cai2+ release during voltage clamp conditions modelled upon time and voltage domains relevant to the cardiac action potential. Here we show that CaMK increases ICa-L after brief positive conditioning pulses, whereas Ca2+-CaM reduces ICa-L over a broad range of positive and negative conditioning potentials. SR Ca2+ release was required for both Ca2+-CaM and CaMK ICa-L responses after strongly positive conditioning pulses (+10 and +40 mV), while Cai2+ from ICa-L was sufficient for Ca2+-CaM during weaker depolarizations. These findings show that ICa-L responses to CaMK are voltage dependent and suggest a new model of L-type Ca2+ channel regulation where voltage-dependent changes control ICa-L responses to Ca2+-CaM and CaMK signalling.

UR - http://www.scopus.com/inward/record.url?scp=0347126405&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347126405&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2003.053314

DO - 10.1113/jphysiol.2003.053314

M3 - Article

C2 - 14678498

AN - SCOPUS:0347126405

VL - 554

SP - 145

EP - 155

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 1

ER -