Phosphoarginine regulation of the squid nerve Na<sup>+</sup>/Ca<sup>2+</sup> exchanger: metabolic pathway and exchanger–ligand interactions different from those seen with ATP

DiPolo, Reinaldo; Berberián, Graciela; Beaugé, Luis

doi:10.1113/jphysiol.2003.050930

Cited by 10 publications

(31 citation statements)

References 25 publications

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“…The large intracellular loop plays a critical role in the ionic and metabolic regulation of the exchanger (88,89,204). Mild proteolysis of the cytosolic side of the exchanger eliminates regulation by intracellular Na ϩ , Ca 2ϩ , H ϩ , and MgATP (91,97,123). The NH 2 -terminal portion of the loop has a 20-amino acid domain rich in hydrophobic and basic amino acids and is called the XIP (exchange inhibitor peptide) region; in addition, it has an overall amino acid sequence similar to the calmodulin-binding domain (190).…”

Section: Structural Characteristics Of the Sodium/calcium Exchangementioning

confidence: 99%

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Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

DiPolo¹,

Beaugé²

2006

Physiological Reviews

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191

157

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The Na+/Ca2+ exchanger's family of membrane transporters is widely distributed in cells and tissues of the animal kingdom and constitutes one of the most important mechanisms for extruding Ca2+ from the cell. Two basic properties characterize them. 1) Their activity is not predicted by thermodynamic parameters of classical electrogenic countertransporters (dependence on ionic gradients and membrane potential), but is markedly regulated by transported (Na+ and Ca2+) and nontransported ionic species (protons and other monovalent cations). These modulations take place at specific sites in the exchanger protein located at extra-, intra-, and transmembrane protein domains. 2) Exchange activity is also regulated by the metabolic state of the cell. The mammalian and invertebrate preparations share MgATP in that role; the squid has an additional compound, phosphoarginine. This review emphasizes the interrelationships between ionic and metabolic modulations of Na+/Ca2+ exchange, focusing mainly in two preparations where most of the studies have been carried out: the mammalian heart and the squid giant axon. A surprising fact that emerges when comparing the MgATP-related pathways in these two systems is that although they are different (phosphatidylinositol bisphosphate in the cardiac and a soluble cytosolic regulatory protein in the squid), their final target effects are essentially similar: Na+-Ca2+-H+ interactions with the exchanger. A model integrating both ionic and metabolic interactions in the regulation of the exchanger is discussed in detail as well as its relevance in cellular Cai2+ homeostasis.

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Section: Structural Characteristics Of the Sodium/calcium Exchangementioning

confidence: 99%

“…(Fig. 35, top) (91). MgATP-ionic interactions occur on the regulatory loop, considered as the "ATP region," whereas the "PA region" is related to the intracellular transporting sites for Na ϩ and Ca…”

mentioning

confidence: 99%

Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

DiPolo¹,

Beaugé²

2006

Physiological Reviews

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191

157

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“…With no changes in the intrinsic affinities of the intracellular transport sites for Na ϩ or Ca 2ϩ , the only feasible explanation seems to involve effects on the Ca i 2ϩ -regulatory site. Actually, this differential inhibition of Ca 2ϩ efflux by Na i ϩ is predicted not only by the steady-state overall cycling scheme described here (see below) but also by the more restricted fast equilibrium scheme of the squid axon model (9,12).…”

Section: Discussionmentioning

confidence: 80%

“…On the other hand, some working assumptions would require different translocation rates of the reversal Na ϩ /Ca 2ϩ and Ca 2ϩ /Ca 2ϩ exchanges, where the first should be slower. Actually this is not the case for the squid axon, where the only limiting branch for translocation, including that at alkaline pH i (8.8), is the entry of Ca 2ϩ (8,12). Other experimental results in dialyzed squid axons also unambiguously show that, provided the Ca i 2ϩ -regulatory site is saturated, neither MgATP nor pH i has any effect on the affinity of the intracellular transport sites for Ca 2ϩ or Na ϩ .…”

Section: Discussionmentioning

confidence: 95%

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Dual effect of Na_i⁺ on Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger in dialyzed squid axons. Experimental data confirming the validity of the squid axon kinetic model

Beaugé¹,

DiPolo²

2008

American Journal of Physiology-Cell Physiology

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We propose a steady-state kinetic model for the squid Na+/Ca2+ exchanger that differs from other current models of regulation in that it takes into account, within a single kinetic scheme, all ionic [intracellular Ca2+ (Cai2+)-intracellular Na+ (Nai+)-intracellular Hi+] and metabolic (ATP) regulations of the exchanger in which the Cai2+-regulatory pathway plays the central role in regulation. Although the integrated ionic-metabolic model predicts all squid steady-state experimental data on exchange regulation, a critical test for the validity of it is the predicted dual effect of Nai+ on steady-state Ca2+ influx through the exchanger. To test this prediction, an improved technique for the estimation of isotope fluxes in squid axons was developed, which allows sequential measurements of ion influx and effluxes. With this method, we report here two novel observations of the squid axon Na+/Ca2+ exchanger. First, at intracellular pH (7.0) and in the absence of MgATP, Nai+ has a dual effect on Ca2+ influx: inhibition at low concentrations followed by stimulation at high Nai+ concentrations, reaching levels higher than those seen without Nai+. Second, in the presence of MgATP, the biphasic response to Nai+ disappears and is replaced by a sigmoid activation. Furthermore, the model predicts that Ca2+ efflux is monotonically inhibited by Nai+, more pronouncedly without than with MgATP. These results are predicted by the proposed kinetic model. Although not fully applicable to all exchangers, this scheme might provide some insights on expected net Ca2+ movements in other tissues under a variety of intracellular ionic and metabolic conditions.

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Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3

Michel

Hoenderop

Bindels

2015

Reviews of Physiology, Biochemistry and Pharmacology

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The Na²⁺-Ca²⁺ exchanger (NCX) is critical for Ca²⁺ homeostasis throughout the body. Of the three isoforms in the NCX family, NCX1 has been extensively studied, providing a good basis for understanding the molecular aspects of the NCX family, including structural resemblances, stoichiometry, and mechanism of exchange. However, the tissue expression of the third isoform of the family, NCX3, together with its proposed involvement in the Ca²⁺ fluxes of the endoplasmic reticulum and the mitochondria suggests a distinctive role for this isoform. Investigations of the exchanger revealed the involvement of NCX3 in diverse processes such as bone formation, TNF-α production, slow-twitch muscle contraction, and long-term potentiation in the hippocampus. Furthermore, the study of its posttranslational modification, its cleavage by the Ca²⁺-sensitive protease, calpain, and its upregulation in numerous stress conditions linked NCX3 to the aberrant Ca²⁺ influx seen during neuronal excitotoxicity in Alzheimer's disease, brain stroke, and neuronal injuries. Hence, beyond its role in calcium homeostasis, NCX3 plays an important role in stress conditions, neuronal excitotoxicity, and metabolism and is thereby a key element in many cell types. The present review aims to survey the knowledge on NCX3, focusing on the recent discoveries on its functional and structural properties, and discusses the implications of NCX3 in both physiological and pathological conditions.

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Phosphoarginine regulation of the squid nerve Na⁺/Ca²⁺ exchanger: metabolic pathway and exchanger–ligand interactions different from those seen with ATP

Abstract: In squid nerves the Na + -Ca 2+ exchanger is up-regulated by ATP and phosphoarginine (PA). ATP regulation involves drastic alterations in the Na

Cited by 10 publications

References 25 publications

Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

Dual effect of Na_i⁺ on Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger in dialyzed squid axons. Experimental data confirming the validity of the squid axon kinetic model

Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3

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Phosphoarginine regulation of the squid nerve Na+/Ca2+ exchanger: metabolic pathway and exchanger–ligand interactions different from those seen with ATP

Abstract: In squid nerves the Na + -Ca 2+ exchanger is up-regulated by ATP and phosphoarginine (PA). ATP regulation involves drastic alterations in the Na

Cited by 10 publications

References 25 publications

Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

Sodium/Calcium Exchanger: Influence of Metabolic Regulation on Ion Carrier Interactions

Dual effect of Nai+ on Ca2+ influx through the Na+/Ca2+ exchanger in dialyzed squid axons. Experimental data confirming the validity of the squid axon kinetic model

Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3

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Phosphoarginine regulation of the squid nerve Na⁺/Ca²⁺ exchanger: metabolic pathway and exchanger–ligand interactions different from those seen with ATP

Dual effect of Na_i⁺ on Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger in dialyzed squid axons. Experimental data confirming the validity of the squid axon kinetic model