Maximal Ca2+i stimulation of cardiac Na+/Ca2+ exchange requires simultaneous alkalinization and binding of PtdIns-4,5-P2 to the exchanger
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Velia Posada
Abstract
Using bovine heart sarcolemma vesicles we studied the effects of protons and phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) on the affinity of the mammalian Na+/Ca2+ exchanger (NCX1) for intracellular Ca2+. By following the effects of extravesicular ligands in inside-out vesicles, their interactions with sites of NCX1 facing the intracellular medium were investigated. Two Na+-gradient-dependent fluxes were studied: Ca2+ uptake and Ca2+ release. PtdIns-4,5-P2 binding to NCX1 was investigated in parallel. Without MgATP (no ‘de novo’ synthesis of PtdIns-4,5-P2), alkalinization increased the affinity for Ca2+ and the PtdIns-4,5-P2 bound to NCX1. Vesicles depleted of phosphoinositides were insensitive to alkalinization, but became responsive following addition of exogenous PtdIns-4,5-P2 or PtdIns plus MgATP. Acidification reduced the affinity for Ca2+ev; this was only partially reversed by MgATP, despite the increase in bound PtdIns-4,5-P2 to levels observed with alkalinization. Inhibition of Ca2+ uptake by increasing extravesicular [Na+] indicates that it is related to H+i and Na+i synergistic inhibition of the Ca2+i regulatory site. Therefore, the affinity of the NCX1 Ca2+i regulatory site for Ca2+ was maximal when both intracellular alkalinization and an increase in PtdIns-4,5-P2 bound to NCX1 (not just of the total membrane PtdIns-4,5-P2) occurred simultaneously. In addition, protons influenced the distribution, or the exposure, of PtdIns-4,5-P2 molecules in the surroundings and/or on the exchanger protein.
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- Supplementary material to the paper “Evolutionary selection pressure and family relationships among connexin genes”
- Evolutionary selection pressure and family relationships among connexin genes
- Characterization of the large subunit of EcoHK31I methyltransferase by structural modeling and mutagenesis
- Purification, characterization, and molecular gene cloning of an antifungal protein from Ginkgo biloba seeds
- Maximal Ca2+i stimulation of cardiac Na+/Ca2+ exchange requires simultaneous alkalinization and binding of PtdIns-4,5-P2 to the exchanger
- A highly conserved protein secreted by the prostate cancer cell line PC-3 is expressed in benign and malignant prostate tissue
- Properties and partial purification of sialate-O-acetyltransferase from bovine submandibular glands
- Raft association and lipid droplet targeting of flotillins are independent of caveolin
- On the presence of C2-ceramide in mammalian tissues: possible relationship to etherphospholipids and phosphorylation by ceramide kinase
- Specific inhibition of interleukin-13 activity by a recombinant human single-chain immunoglobulin domain directed against the IL-13 receptor α1 chain
- Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S
- Compartmentalised expression of meprin in small intestinal mucosa: enhanced expression in lamina propria in coeliac disease
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