期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 97, 期 22, 页码 12334-12338出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.210384297
关键词
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资金
- NHLBI NIH HHS [P01 HL044948, P01 HL44948] Funding Source: Medline
We have investigated the mechanism underlying the modulation of the cardiac L-type Ca2+ current by protein kinase C (PKC). Using the patch-clamp technique, we found that PKC activation by 4-alpha -phorbol 12-myristate 13-acetate (PMA) or rac-1-oleyl-2-acetyl-glycerol (OAG) caused a substantial reduction in Ba2+ current through Ca(v)1.2 channels composed of alpha (1)1.2, beta (1b), and alpha (2)delta (1) subunits expressed in tsA-201 cells. In contrast, Ba2+ current through a cloned brain isoform of the Ca(v)1.2 channel (rbC-11) was unaffected by PKC activation. Two potential sites of PKC phosphorylation are present at positions 27 and 31 in the cardiac form of Ca(v)1.2, but not in the brain form. Deletion of N-terminal residues 2-46 prevented PKC inhibition. Conversion of the threonines at positions 27 and 31 to alanine also abolished the PKC sensitivity of Ca(v)1.2. Mutant Ca(v)1.2 channels in which the threonines were converted singly to alanines were also insensitive to PKC modulation, suggesting that phosphorylation of both residues is required for PKC-dependent modulation. Consistent with this, mutating each of the threonines individually to aspartate in separate mutants restored the PKC sensitivity, of Ca(v)1.2, indicating that a change in net charge by phosphorylation of both sites is responsible for inhibition. Our results define the molecular basis for inhibition of cardiac Ca(v)1.2 channels by the PKC pathway.
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