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 E.
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.
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U2 - 10.1113/jphysiol.2003.053314
DO - 10.1113/jphysiol.2003.053314
M3 - Article
C2 - 14678498
AN - SCOPUS:0347126405
SN - 0022-3751
VL - 554
SP - 145
EP - 155
JO - Journal of Physiology
JF - Journal of Physiology
IS - 1
ER -