CSN5/Jab1 inhibits cardiac L-type Ca2+ channel activity through protein-protein interactions.
L-type Ca(2+) channels have a wide tissue distribution and play essential roles in physiological responses. Recent studies have indicated that regulation of L-type Ca(2+) channels involves the assembly of macromolecular signaling complexes such as the beta(2)-adrenergic receptor signaling complex, the small G-protein kir/Gem and the BK channel. Here, we report the previously unidentified role of another protein in binding to the II-III linker of the alpha(1C) subunit of the L-type Ca(2+) channel. This protein is COP9 signalosome subunit 5 (CSN5)/Jun activation domain-binding protein 1 (Jab1). We have demonstrated that CSN5 interacts specifically with the II-III linker of the alpha(1C) subunit in a yeast two-hybrid system. The alpha(1C) subunit and CSN5 were coimmunoprecipitated in rat heart and both proteins were colocalized in sarcolemmal membranes and transverse tubules of cardiac myocytes. Silencing of CSN5 mRNA using siRNA decreased the endogenous protein level of CSN5 and activated L-type Ca(2+) channels expressed in COS7 cells. These data indicate that CSN5 is a protein that plays a newly defined functional role in association with the cardiac L-type Ca(2+) channel.
Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
Kazutoshi
K
Kameda
Mitsuhiro
M
Fukao
Takeshi
T
Kobayashi
Masaaki
M
Tsutsuura
Masato
M
Nagashima
Yoichi
Y
Yamada
Toshihiko
T
Yamashita
Noritsugu
N
Tohse
D000818:Animals; D000075686:COP9 Signalosome Complex; D019556:COS Cells; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D021122:Protein Subunits; D018343:Receptors, Adrenergic, beta-2; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex