S-palmitoylation and the regulation of NCX1

Fuller, William; Reilly, Louise; Hilgemann, Donald W.

doi:10.1080/19336950.2015.1099329

Cited by 24 publications

(42 citation statements)

References 8 publications

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“…Indeed, trans-sarcolemmal fluxes of Na, Ca and K ions are all influenced by palmitoylation of the transporters and channels involved. The cardiac sodium/calcium exchanger NCX1 is palmitoylated at a single cysteine in its large regulatory intracellular loop, which sensitizes it to inhibition by its integral 'exchange inhibitory peptide' (Reilly et al, 2015, Fuller et al, 2016. Palmitoylation of cysteines in the II-III linker of voltage-gated channel sodium SCN5a, which is responsible for the voltage activated Na current that initiates the cardiac action potential, increases channel availability and hence cardiac excitability (Pei et al, 2016).…”

Section: Palmitoylation and The Regulation Of Cardiac Ion Transportersmentioning

confidence: 99%

“…Palmitoylation of NCX1, for example, sensitizes it to depletion of PIP2 (Reilly et al, 2015, Fuller et al, 2016, while more generally palmitoylation of integral membrane proteins regulates their affinity for lipid rafts (Levental et al, 2010a, Levental et al, 2010b. Like all ion transporters the Na pump interacts with and is influenced by lipids.…”

Section: Pump-phospholipid Interactionsmentioning

confidence: 99%

“…Calcium overload leading to mitochondrial stress causes transient openings of the mitochondrial permeability transition pore (MPTP), releasing of coenzyme A into the cytoplasm where it is acylated to form a substrate for DHHC5 to palmitoylate surface membrane proteins (Hilgemann et al, 2013). The clustering of acylated proteins in lipid ordered domains leads to MEND by as-yet unidentified mechanisms in multiple cells types (Reilly et al, 2015, Fuller et al, 2016.…”

Section: Massive Endocytosis the Role Of Dhhc5 In Cellular And Cardimentioning

confidence: 99%

“…Hence palmitoylation of cardiac substrates by DHHC5 controls cellular processes that underlie a significant worldwide health burden. Of particular relevance to the cardiac Na pump and cardiac ion transport in general is the finding that this type of endocytosis preferentially internalizes pumps and ion transporters, probably because these proteins have bulky intracellular and small extracellular regions that favor their clustering in invaginated curved membrane domains (Reilly et al, 2015, Fuller et al, 2016. Indeed, palmitoylated proteins prefer to reside in such highly curved membranes (Larsen et al, 2015).…”

Section: Massive Endocytosis the Role Of Dhhc5 In Cellular And Cardimentioning

confidence: 99%

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Greasing the wheels or a spanner in the works? Regulation of the cardiac sodium pump by palmitoylation

Howie

Wypijewski

Plain

et al. 2018

Critical Reviews in Biochemistry and Molecular Biology

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The ubiquitous sodium/potassium ATPase (Na pump) is the most abundant primary active transporter at the cell surface of multiple cell types, including ventricular myocytes in the heart. The activity of the Na pump establishes transmembrane ion gradients that control numerous events at the cell surface, positioning it as a key regulator of the contractile and metabolic state of the myocardium. Defects in Na pump activity and regulation elevate intracellular Na in cardiac muscle, playing a causal role in the development of cardiac hypertrophy, diastolic dysfunction, arrhythmias and heart failure. Palmitoylation is the reversible conjugation of the fatty acid palmitate to specific protein cysteine residues; all subunits of the cardiac Na pump are palmitoylated. Palmitoylation of the pump's accessory subunit phospholemman (PLM) by the cell surface palmitoyl acyl transferase DHHC5 leads to pump inhibition, possibly by altering the relationship between the pump catalytic α subunit and specifically bound membrane lipids. In this review, we discuss the functional impact of PLM palmitoylation on the cardiac Na pump and the molecular basis of recognition of PLM by its palmitoylating enzyme DHHC5, as well as effects of palmitoylation on Na pump cell surface abundance in the cardiac muscle. We also highlight the numerous unanswered questions regarding the cellular control of this fundamentally important regulatory process.

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Section: Palmitoylation and The Regulation Of Cardiac Ion Transportersmentioning

confidence: 99%

Section: Pump-phospholipid Interactionsmentioning

confidence: 99%

Section: Massive Endocytosis the Role Of Dhhc5 In Cellular And Cardimentioning

confidence: 99%

Section: Massive Endocytosis the Role Of Dhhc5 In Cellular And Cardimentioning

confidence: 99%

See 2 more Smart Citations

Greasing the wheels or a spanner in the works? Regulation of the cardiac sodium pump by palmitoylation

Howie

Wypijewski

Plain

et al. 2018

Critical Reviews in Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…NCX1 is palmitoylated at a single cysteine in this regulatory loop: unpalmitoylated exchangers are resistant to inactivation and retain substantial activity when wild type exchangers inactivate. 4,5 There are multiple cysteines in the NCX1 regulatory loop but only cysteine 739, located at the C-terminal end of this loop close to transmembrane domain 6, becomes palmitoylated. In our recent paper 6 we asked why this particular cysteine gets palmitoylated when neighboring ones do not.…”

Section: Palmitoylation Of Ncx1mentioning

confidence: 99%