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Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

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Abstract

Plasma membrane Ca2+ pumps (PMCA) extrude cellular Ca2+ with a high affinity and hence play a major role in Ca2+ homeostasis and signaling. Caloxins (selective extracellular PMCA inhibitors) would aid in elucidating the physiology of PMCA. PMCA proteins have five extracellular domains (exdoms). Our hypotheses are: 1) peptides that bind selectively to each exdom can be invented by screening a random peptide library, and 2) a peptide can modulate PMCA activity by binding to one of the exdoms. The first caloxin 2a1, selected for binding exdom 2 was selective for PMCA (Ki = 529 μM). It has been used to examine the physiological role of PMCA. PMCA isoforms are encoded by four genes. PMCA isoform expression differs in various cell types, with PMCA1 and 4 being the most widely distributed. There are differences between PMCA1-4 exdom 1 sequences, which may be exploited for inventing isoform selective caloxins. Using exdom 1 of PMCA4 as a target, modified screening procedures and mutagenesis led to the high-affinity caloxin 1c2 (Ki = 2.3 μM for PMCA4). It is selective for PMCA4 over PMCA1, 2, or 3. We hope that caloxins can be used to discern the roles of individual PMCA isoforms in Ca2+ homeostasis and signaling. Caloxins may also become clinically useful in cardiovascular diseases, neurological disorders, retinopathy, cancer, and contraception.

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Abbreviations

Ca2+i:

cytosolic [Ca2+]

Exdom:

extracellular domain

nNOS:

neuronal nitric oxide synthase

NCX:

Na+-Ca2+ exchanger

PM:

plasma membrane

PMCA:

plasma membrane Ca2+ pump

SERCA:

sarco/endoplasmic reticulum Ca2+ pump

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Acknowledgements

This work was supported by a Grant-in-Aid (NA5783) from the Heart & Stroke Foundation of Ontario. This work is dedicated to Dr. M. Kapoor (Calgary University, Calgary) who taught AKG how to do research and to Dr. E. E. Daniel (University of Alberta) who introduced him to PMCA.

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  1. Department of Medicine, McMaster University, HSC 4N41, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    Ashok K. Grover

  2. Department of Biology, McMaster University, HSC 4N41, 1200 Main Street W, Hamilton, ON, L8N3Z5, Canada

    Magdalena M. Szewczyk, Jyoti Pande & Ashok K. Grover

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  1. Magdalena M. Szewczyk
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  2. Jyoti Pande
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  3. Ashok K. Grover
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Correspondence to Ashok K. Grover.

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Szewczyk, M.M., Pande, J. & Grover, A.K. Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology. Pflugers Arch - Eur J Physiol 456, 255–266 (2008). https://doi.org/10.1007/s00424-007-0348-6

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