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Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+ -binding function of a motif with similarity to Ca2+ -binding domains.

ABSTRACT: alpha(1C)- and alpha(1E)-based Ca2+ channels differ in that the former are inhibited by Ca2+ entering through its pore, while the latter are not. It has been proposed on the basis of analysis of alpha(1E)/alpha(1C) chimeras that the molecular determinants responsible for Ca2+ inhibition involve both a conserved Ca2+-binding motif (EF hand) plus additional sequences located C-terminal to the EF hand. Through construction of similar alpha(1E)/alpha(1C) chimeras, we transferred Ca2+ inhibition from alpha(1C) to alpha(1E) by replacing a 134-aa segment of alpha(1E) with the homologous 142-aa segment of alpha(1C). This segment is located immediately after the proposed Ca2+ -binding EF hand motif. Replacement of the alpha(1C) EF hand with the corresponding EF hand of alpha(1E) did not interfere with inhibition of alpha(1C) by Ca2+, and a triple mutant of alpha(1C), alpha(1C)[D1535A,E1537A,D1546A], that disrupts the potential Ca2+-coordinating ability of the EF hand continued to be inhibited by Ca2+. These results indicate that a small portion of the alpha(1C) C terminus is essential for inhibition by Ca2+ and place the Ca2+ -binding site anywhere in alpha(1C), with the exception of its EF hand-like motif.

SUBMITTER: Zhou J

PROVIDER: S-EPMC20082 | biostudies-literature | 1997 Mar

REPOSITORIES: biostudies-literature

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Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+ -binding function of a motif with similarity to Ca2+ -binding domains.

Zhou J J Olcese R R Qin N N Noceti F F Birnbaumer L L Stefani E E

Proceedings of the National Academy of Sciences of the United States of America 19970301 6

alpha(1C)- and alpha(1E)-based Ca2+ channels differ in that the former are inhibited by Ca2+ entering through its pore, while the latter are not. It has been proposed on the basis of analysis of alpha(1E)/alpha(1C) chimeras that the molecular determinants responsible for Ca2+ inhibition involve both a conserved Ca2+-binding motif (EF hand) plus additional sequences located C-terminal to the EF hand. Through construction of similar alpha(1E)/alpha(1C) chimeras, we transferred Ca2+ inhibition from ...[more]

PMID: 9122189

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Project description:A major contributing factor to the high mortality rate associated with acute myeloid leukemia and multiple myeloma is the development of resistance to chemotherapy. We have shown that the combination of tipifarnib, a nonpeptidomimetic farnesyltransferase inhibitor (FTI), with bortezomib, a proteosome inhibitor, promotes synergistic death and overcomes de novo drug resistance in acute myeloid leukemia cell lines. Experiments were undertaken to identify the molecular mechanisms by which tipifarnib produces cell death in acute myeloid leukemia and multiple myeloma cell lines (U937 and 8226, respectively). Tipifarnib, but not other FTIs tested [N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) and 2'-methyl-5-((((1-trityl-1H-imidazol-4-yl)methyl)amino)methyl)-[1,1'-biphenyl]-2-carboxylic acid (FTI-2153), promotes elevations in intracellular free-calcium concentrations ([Ca(2+)](i)) in both cell lines. These elevations in [Ca(2+)](i) were accompanied by highly dynamic plasmalemmal blebbing and frequently resulted in membrane lysis. The tipifarnib-induced elevations in [Ca(2+)](i) were not blocked by thapsigargin or ruthenium red, but were inhibited by application of Ca(2+)-free extracellular solution and by the Ca(2+) channel blockers Gd(3+) and La(3+). Conversely, 2-aminoethoxydiphenyl borate (2-APB) potentiated the tipifarnib-evoked [Ca(2+)](i) overload. Preventing Ca(2+) influx diminished tipifarnib-evoked cell death, whereas 2-APB potentiated this effect, demonstrating a link between tipifarnib-induced Ca(2+) influx and apoptosis. These data suggest that tipifarnib exerts its effects by acting on a membrane channel with pharmacological properties consistent with store-operated channels containing the Orai3 subunit. It is noteworthy that Orai3 transcripts were found to be expressed at lower levels in tipifarnib-resistant 8226/R5 cells. Our results indicate tipifarnib causes cell death via a novel mechanism involving activation of a plasma membrane Ca(2+) channel and intracellular Ca(2+) overload.

Dataset Information

Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+ -binding function of a motif with similarity to Ca2+ -binding domains.

Publications

Feedback inhibition of Ca2+ channels by Ca2+ depends on a short sequence of the C terminus that does not include the Ca2+ -binding function of a motif with similarity to Ca2+ -binding domains.

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