Journal
FRONTIERS IN CELLULAR NEUROSCIENCE
Volume 15, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2021.668371
Keywords
calcium transport; calcium ATPase; PMCA isoforms; neuronal PMCA; heart PMCA
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2017-1690]
- Consejo Nacional de Investigaciones Cientificas y Tecnologicas [PIP 2015-773]
- Universidad de Buenos Aires UBACyT
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PMCA isoforms control Ca2+ signaling by transporting Ca2+ out of eukaryotic cells. PMCA4 has two A splice variants, x and z, with z showing higher ATPase activity and greater sensitivity to acidic lipids compared to x.
The plasma membrane Ca2+ pumps (PMCA) are P-ATPases that control Ca2+ signaling and homeostasis by transporting Ca2+ out of the eukaryotic cell. Humans have four genes that code for PMCA isoforms (PMCA1-4). A large diversity of PMCA isoforms is generated by alternative mRNA splicing at sites A and C. The different PMCA isoforms are expressed in a cell-type and developmental-specific manner and exhibit differential sensitivity to a great number of regulatory mechanisms. PMCA4 has two A splice variants, the forms x and z. While PMCA4x is ubiquitously expressed and relatively well-studied, PMCA4z is less characterized and its expression is restricted to some tissues such as the brain and heart muscle. PMCA4z lacks a stretch of 12 amino acids in the so-called A-M3 linker, a conformation-sensitive region of the molecule connecting the actuator domain (A) with the third transmembrane segment (M3). We expressed in yeast PMCA4 variants x and z, maintaining constant the most frequent splice variant b at the C-terminal end, and obtained purified preparations of both proteins. In the basal autoinhibited state, PMCA4zb showed a higher ATPase activity and a higher apparent Ca2+ affinity than PMCA4xb. Both isoforms were stimulated by calmodulin but PMCA4zb was more strongly activated by acidic lipids than PMCA4xb. The results indicate that a PMCA4 intrinsically more active and more responsive to acidic lipids is produced by the variant z of the splicing site A.
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