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(Circulation Research. 2004;94:1242.)
© 2004 American Heart Association, Inc.

Cellular Biology

Leukemia Inhibitory Factor Activates Cardiac L-Type Ca²⁺ Channels via Phosphorylation of Serine 1829 in the Rabbit Ca_v1.2 Subunit

Eiichi Takahashi, Keiichi Fukuda, Shunichiro Miyoshi, Mitsushige Murata, Takahiro Kato, Makoto Ita, Tsutomu Tanabe, Satoshi Ogawa

From the Institute for Advanced Cardiac Therapeutics (E.T., K.F., S.M.), Cardiopulmonary Division, Department of Internal Medicine (M.M., T.K., S.O.), and Pharmacia-Keio Research Laboratories (M.I.), Shinanomachi Research Park, Keio University School of Medicine, and Department of Pharmacology and Neurobiology (T.T.), Graduate School of Medicine, Tokyo Medical and Dental University, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan.

Correspondence to Keiichi Fukuda, MD, PhD, Institute for Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

We have previously reported that leukemia inhibitory factor (LIF) gradually increased cardiac L-type Ca²⁺ channel current (I_CaL), which peaked at 15 minutes in both adult and neonatal rat cardiomyocytes, and this increase was blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. This study investigated the molecular basis of LIF-induced augmentation of I_CaL in rodent cardiomyocytes. LIF induced phosphorylation of a serine residue in the _1c subunit (Ca_v1.2) of L-type Ca²⁺ channels in cultured rat cardiomyocytes, and this phosphorylation was inhibited by PD98059. When constructs encoding either a wild-type or a carboxyl-terminal–truncated rabbit Ca_v1.2 subunit were transfected into HEK293 cells, LIF induced phosphorylation of the resultant wild-type protein but not the mutant protein. Cotransfection of constitutively active mitogen-activated protein kinase kinase also resulted in phosphorylation of the Ca_v1.2 subunit in the absence of LIF stimulation. In in-gel kinase assays, extracellular signal–regulated kinase phosphorylated a glutathione S-transferase fusion protein of the carboxyl-terminal region of Ca_v1.2 (residues 1700 through 1923), which contains the consensus sequence Pro-Leu-Ser-Pro. A point mutation within this consensus sequence, which results in a substitution of alanine for serine at residue 1829 (S1829A), was sufficient to abolish the LIF-induced phosphorylation. LIF increased I_CaL in HEK cells transfected with wild-type Ca_v1.2 but not with the mutated version. These results provide direct evidence that LIF phosphorylates the serine residue at position 1829 of the Ca_v1.2 subunit via the actions of extracellular signal–regulated kinase and that this phosphorylation increases I_CaL in cardiomyocytes.

Key Words: cardiomyocytes • extracellular signal–regulated kinase • leukemia inhibitory factor • L-type Ca²⁺ channels • phosphorylation

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