Regulation of the cardiac Na+ pump by palmitoylation of its catalytic and regulatory subunits

Howie, J. W.; Tulloch, L.B.; Shattock, Michael J.; Fuller, William

doi:10.1042/bst20120269

Cited by 23 publications

(22 citation statements)

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“…We have previously speculated that given the orientation of PLM C42 toward the pump α-subunit, palmitoylation at this site rather than PLM C40 mediates pump inhibition by palmitoylated PLM (10). That this is unequivocally not the case is one conclusion of the present investigation: PLMmediated inhibition of the Na pump absolutely requires its palmitoylation at C40.…”

Section: Discussionmentioning

confidence: 41%

“…Interestingly, MEND is accelerated in the presence of the Na pump regulatory subunit phospholemman (PLM) (7), which inhibits the Na pump when palmitoylated (9,10), activates the pump when phosphorylated (11,12), and relieves the pump from oxidative inhibition by becoming glutathionylated (13). The biochemical interplay of multiple posttranslational modifications on this small protein is complex.…”

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confidence: 99%

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Substrate recognition by the cell surface palmitoyl transferase DHHC5

Howie

Reilly

Fraser

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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106

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The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discslarge/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme-substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump.phospholemman | sodium pump | palmitoylation | DHHC | ion transport P rotein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol via a thioester bond, is catalyzed by Asp-His-His-Cys motif-containing palmitoyl acyltransferases (DHHC-PATs); there are 23 human isoforms (1). These zinc-finger-containing enzymes typically have four transmembrane (TM) domains, with a conserved ∼50 amino acid cysteine-rich cytosolic core located between TM2 and -3, which contains a conserved DHHC motif, the active site. In contrast, the intracellular amino and carboxyl termini are poorly conserved, and likely contribute to DHHC isoform substrate selectivity (1). DHHC-PATs are expressed throughout the secretory pathway, but DHHC5 is widely recognized as one of very few cell-surfacelocalized PATs (2, 3). The final four amino acids of DHHC5 form a canonical class II PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, which interacts with postsynaptic density protein 95 (PSD-95) (2), although PSD-95 is not itself a DHHC5 substrate.An appreciation is now growing that protein palmitoylation turns over rapidly (in minutes) for certain proteins (4-8). For example, dynamic surface membrane protein palmitoylation by DHHC5 underlies a novel form of endocytosis, massive endocytosis (MEND), in which up to 70% of the cell surface membrane is internalized (7, 8). Calci...

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Section: Discussionmentioning

confidence: 41%

mentioning

confidence: 99%

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Howie

Reilly

Fraser

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

157

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“…Palmitoylation, mediated by LRAT, can increase targeted regional hydrophobicity and is an expected requisite for a massive influx of ion channels into a cell membrane. However, although at least three subunits of the human cardiac sodium pump are regulated by palmitoylation, the full functional outcome of these palmitoylation events is still not well characterized (Howie et al, 2013). The increased targeting of ion pumps into Chloroidium sp.…”

Section: Discussionmentioning

confidence: 99%

The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization

Nelson

Khraiwesh

et al. 2017

eLife

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To investigate the phenomic and genomic traits that allow green algae to survive in deserts, we characterized a ubiquitous species, Chloroidium sp. UTEX 3007, which we isolated from multiple locations in the United Arab Emirates (UAE). Metabolomic analyses of Chloroidium sp. UTEX 3007 indicated that the alga accumulates a broad range of carbon sources, including several desiccation tolerance-promoting sugars and unusually large stores of palmitate. Growth assays revealed capacities to grow in salinities from zero to 60 g/L and to grow heterotrophically on >40 distinct carbon sources. Assembly and annotation of genomic reads yielded a 52.5 Mbp genome with 8153 functionally annotated genes. Comparison with other sequenced green algae revealed unique protein families involved in osmotic stress tolerance and saccharide metabolism that support phenomic studies. Our results reveal the robust and flexible biology utilized by a green alga to successfully inhabit a desert coastline.DOI: http://dx.doi.org/10.7554/eLife.25783.001

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“…; Howie et al . ). Oxidant stress and modification of NKA thiols has long been known to inhibit the NKA activity (Shattock & Matsuura, ; Haddock et al .…”

Section: The Na+/ca2+ Exchanger – Structure Function and Regulationmentioning

confidence: 97%

Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart

Shattock

Ottolia

Bers

et al. 2015

The Journal of Physiology

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This paper is the third in a series of reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias: Na+ channel and Na+ transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on cardiac Na+/Ca2+ exchange (NCX) and Na+/K+-ATPase (NKA). While the relevance of Ca2+ homeostasis in cardiac function has been extensively investigated, the role of Na+ regulation in shaping heart function is often overlooked. Small changes in the cytoplasmic Na+ content have multiple effects on the heart by influencing intracellular Ca2+ and pH levels thereby modulating heart contractility. Therefore it is essential for heart cells to maintain Na+ homeostasis. Among the proteins that accomplish this task are the Na+/Ca2+ exchanger (NCX) and the Na+/K+ pump (NKA). By transporting three Na+ ions into the cytoplasm in exchange for one Ca2+ moved out, NCX is one of the main Na+ influx mechanisms in cardiomyocytes. Acting in the opposite direction, NKA moves Na+ ions from the cytoplasm to the extracellular space against their gradient by utilizing the energy released from ATP hydrolysis. A fine balance between these two processes controls the net amount of intracellular Na+ and aberrations in either of these two systems can have a large impact on cardiac contractility. Due to the relevant role of these two proteins in Na+ homeostasis, the emphasis of this review is on recent developments regarding the cardiac Na+/Ca2+ exchanger (NCX1) and Na+/K+ pump and the controversies that still persist in the field.

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Regulation of the cardiac Na+ pump by palmitoylation of its catalytic and regulatory subunits

Cited by 23 publications

References 46 publications

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Substrate recognition by the cell surface palmitoyl transferase DHHC5

The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization

Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart

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Regulation of the cardiac Na+ pump by palmitoylation of its catalytic and regulatory subunits

Cited by 23 publications

References 46 publications

Substrate recognition by the cell surface palmitoyl transferase DHHC5

Substrate recognition by the cell surface palmitoyl transferase DHHC5

The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization

Na+/Ca2+ exchange and Na+/K+‐ATPase in the heart

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Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart