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Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca2+-pump isoform 4, on coronary artery

Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca2+-pump isoform 4, on coronary artery

Authors :
Jyoti Pande
Iwona Kuszczak
Emanuel Escher
Shawn Grover
Magdalena M. Szewczyk
Ashok K. Grover
Source :
Journal of Cellular and Molecular Medicine
Publication Year :
2008
Publisher :
Wiley, 2008.

Abstract

Coronary artery smooth muscle expresses the plasma membrane Ca(2+) pump (PMCA) isoforms PMCA4 and PMCA1. We previously reported the peptide inhibitor caloxin 1b1 that was obtained by using extracellular domain 1 of PMCA4 as the target (Am J Physiol Cell.290 [2006] C1341). To engineer inhibitors with greater affinity and isoform selectivity, we have now created a phage display library of caloxin 1b1-like peptides. We screened this library by affinity chromatography with PMCA from erythrocyte ghosts that contain mainly PMCA4 to obtain caloxin 1c2. Key properties of caloxin 1c2 are (a) Ki = 2.3 +/- 0.3 microM which corresponds to a 20x higher affinity for PMCA4 than that of caloxin 1b1 and (b) it is selective for PMCA4 since it has greater than 10-fold affinity for PMCA4 than for PMCA1, 2 or 3. It had the following functional effects on coronary artery smooth muscle: (a) it increased basal tone of the de-endothelialized arteries; the increase being similar at 10, 20 or 50 microM, and (b) it enhanced the increase in the force of contraction at 0.05 but not at 1.6 mM extracellular Ca(2+) when Ca(2+) extrusion via the Na(+)-Ca(2+) exchanger and the sarco/endoplasmic reticulum Ca(2+) pump were inhibited. We conclude that PMCA4 is pivotal to Ca(2+) extrusion in coronary artery smooth muscle. We anticipate caloxin 1c2 to aid in understanding the role of PMCA4 in signal transduction and home-ostasis due to its isoform selectivity and ability to act when added extracellularly.

Details

ISSN :
15821838
Volume :
12
Database :
OpenAIRE
Journal :
Journal of Cellular and Molecular Medicine
Accession number :
edsair.doi.dedup.....ddb4aa6e4263f6cfd4ab3926aa1a0a1c
Full Text :
https://doi.org/10.1111/j.1582-4934.2008.00140.x