Forefront of Na+/Ca2+ Exchanger Studies: Stoichiometry of Cardiac Na+/Ca2+ Exchanger; 3:1 or 4:1?

Hinata, Masamitsu; Kimura, Junko

doi:10.1254/jphs.fmj04002x3

Cited by 19 publications

(15 citation statements)

References 23 publications

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“…Rat heart position shifts during data acquisition were observed with hypoxia onset; however, they were neither sufficient to fully remove a region-of-interest (ROI) from the fieldof-view (FOV) nor drastic enough to completely alter the geometry of the arrested myocardium (one heart in the group that was perfused with 25 mM Mn 2þ contracted twice during the data acquisition period). Statistical analyses were based on the first (normoxia; s ¼ [1,10]) and last (hypoxia; s ¼ [31,40]) 10 scans whereas time-series (TS) analyses relied on all observations. In the figures that follow, each pharmacokinetic TS datum abscissal coordinate reflects the mid-point of its $3.5 min acquisition period whereas the ordinate values of the accompanying red traces represent 95% confidence interval (CI) bounds.…”

Section: Resultsmentioning

confidence: 99%

“…Group mean X nsr [ --X sr ] distributions were then generated by sampling the N X nsr distributions within each group and then averaging the resulting distribution. In the TS context, this sampling was specific to each individual scan; in the statistical analyses however, the sampling encompassed s ¼ [1,10] and s ¼ [31,40] during normoxia and hypoxia, respectively, yielding, X r (as opposed to X sr ). The expected TS property value at each scan s, i.e.…”

Section: Mri Scanning and Data Processingmentioning

confidence: 99%

“…whereas the expected X r values for normoxia (s ¼ [1, 10]) or hypoxia (s ¼ [31,40]) were estimated with eqn (3),…”

Section: Mri Scanning and Data Processingmentioning

confidence: 99%

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Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Medina

Kirkland

Tavazoie

et al. 2007

Contrast Media & Molecular

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Paramagnetic Mn2+ has emerged in the search for non-invasive magnetic resonance imaging (MRI) techniques to monitor Ca2+ in diagnostic and prognostic cardiovascular disease tests because it both alters MRI contrast and behaves as a Ca2+ 'surrogate' in vivo. However, the reliance on macroscopically averaged measurements to infer microscopic processes constitutes a major limitation of MRI. This investigation circumvents this limitation and contributes an MRI-based myocardial Ca2+-transporter assay, which probes the Na+/Ca2+-exchanger involvement in Mn2+ (and presumably Ca2+) transport by virtue of its response to pharmacological inhibition. In the model employed herein, ex vivo arrested rat hearts underwent normoxia and then hypoxia while a constant (hyperkalemic) perfusion minimized flow (and uncontrolled Ca2+-channel) contributions to Mn2+-enhanced MRI measurements. The results (i) demonstrate that Mn2+ (and presumably Ca2+) accumulates via Na+/Ca2+-exchanger-mediated transport during hyperkalemic hypoxia and further, (ii) implicate hypo-perfusion (rather than the diminished participation of an isolated sarcolemmal Ca2+-transporter) as the mechanism that underlies the reported reductions of Mn2+ accumulation (relative to healthy myocardium) subsequent to myocardial insults in MRI studies. Although myriad studies have employed Mn2+-enhanced MRI in myocardial investigations, this appears to be the first attempt to assay the Na+/Ca2+-exchanger with MRI under highly circumscribed conditions. MRI-based Ca2+)transporter assays, such as the Na+/Ca2+-exchanger assay utilized here, will inevitably impact disciplines in the medical sciences and beyond.

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Section: Resultsmentioning

confidence: 99%

Section: Mri Scanning and Data Processingmentioning

confidence: 99%

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Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Medina

Kirkland

Tavazoie

et al. 2007

Contrast Media & Molecular

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“…It is well established that NCXs are reversible and electrogenic, but it has been debated whether the Na + /Ca 2+ exchange stoichiometry is 3:1 or 4:1 (3,5,(7)(8)(9)(10)(11)(12). In any case, NCXs can also facilitate Na + /Na + and Ca 2+ /Ca 2+ exchange, implying that the translocation of Na + and Ca 2+ are two distinct reactions (3,5,6,13).…”

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confidence: 99%

Sodium recognition by the Na ⁺ /Ca ²⁺ exchanger in the outward-facing conformation

Marinelli

Almagor

Hiller

et al. 2014

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

124

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Na + /Ca 2+ exchangers (NCXs) are ubiquitous membrane transporters with a key role in Ca 2+ homeostasis and signaling. NCXs mediate the bidirectional translocation of either Na + or Ca 2+ , and thus can catalyze uphill Ca 2+ transport driven by a Na + gradient, or vice versa. In a major breakthrough, a prokaryotic NCX homolog (NCX_Mj) was recently isolated and its crystal structure determined at atomic resolution. The structure revealed an intriguing architecture consisting of two inverted-topology repeats, each comprising five transmembrane helices. These repeats adopt asymmetric conformations, yielding an outward-facing occluded state. The crystal structure also revealed four putative ion-binding sites, but the occupancy and specificity thereof could not be conclusively established. Here, we use molecular-dynamics simulations and free-energy calculations to identify the ion configuration that best corresponds to the crystallographic data and that is also thermodynamically optimal. In this most probable configuration, three Na + ions occupy the so-called S ext , S Ca , and S int sites, whereas the S mid site is occupied by one water molecule and one H + , which protonates an adjacent aspartate side chain (D240). Experimental measurements of Na + /Ca 2+ and Ca 2+ /Ca 2+ exchange by wild-type and mutagenized NCX_Mj confirm that transport of both Na + and Ca 2+ requires protonation of D240, and that this side chain does not coordinate either ion at S mid . These results imply that the ion exchange stoichiometry of NCX_Mj is 3:1 and that translocation of Na + across the membrane is electrogenic, whereas transport of Ca 2+ is not. Altogether, these findings provide the basis for further experimental and computational studies of the conformational mechanism of this exchanger.secondary transporters | membrane antiporters | ion specificity | CaCA superfamily | molecular-dynamics simulations C a 2+ signals control a variety of cellular processes essential for the basic function of multiple organs. In cardiac cells, for example, Ca 2+ release from the sarcoplasmic reticulum is a necessary step for heart contraction, whereas Ca 2+ extrusion from the cell is required for cardiac relaxation. These fluctuations in the cytosolic Ca 2+ concentration underlie the initiation of the heartbeat (1, 2). Na + /Ca 2+ exchangers (NCXs) play a central role in the homeostasis of cellular Ca 2+ (3-5). These integral membrane proteins are ubiquitous in many types of tissues including the heart, brain, and kidney (4), and consequently their dysfunction is associated with numerous human pathologies such as cardiac arrhythmia, hypertension, skeletal muscle dystrophy, and postischemic brain damage (5). NCXs facilitate the translocation of either Ca 2+ or Na + across the membrane; thus, they can harness a transmembrane sodium motive force to energize Ca 2+ transport against a concentration gradient. For example, the cardiac exchanger NCX1 mediates the extrusion of intracellular Ca 2+ driven by a Na + transmembrane gradient maintained by the Na ...

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“…Na + entry has been implicated in physiological Ca 2+ signaling phenomena such as Ca 2+ oscillations [21,22] and in pathophysiological Ca 2+ overload [23]. The key signaling element, which serves as a link between Na + and Ca 2+ homeostasis, is the plasma membrane Na + / Ca 2+ exchanger (NCX), which transports Na + in exchange for Ca 2+ with a stoichiometry of 3:1 [24]. Driving force and direction of this transport is determined by the concentration gradient for Na + and Ca 2+ and the membrane potential, with a reversal potential (E NCX ) given by: E NCX =3E Na ÀE Ca.…”

Section: Introductionmentioning

confidence: 99%

Na+ entry and modulation of Na+/Ca2+ exchange as a key mechanism of TRPC signaling

Eder

Poteser

Romanin

et al. 2005

Pflugers Arch - Eur J Physiol

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Ion channels formed by canonical transient receptor potential (TRPC) proteins are considered to be key players in cellular Ca(2+) homeostasis. As permeation of Ca(2+) through TRPC homo- and/or heteromeric channels has been repeatedly demonstrated, analysis of the physiological role of TRPC proteins was so far based on the concept that these proteins form regulated Ca(2+) entry channels. The well-recognized lack of cation selectivity of TRPC channels and the ability to generate substantial monovalent conductances that govern membrane potential and cation gradients were barely appreciated as a physiologically relevant issue. Nonetheless, recent studies suggest monovalent, specifically Na(+) permeation through TRPC cation channels as an important event in TRPC signaling. TRPC-mediated Na(+) entry may be converted into a distinct pattern of cellular Ca(2+) signals by interaction with Na(+)/Ca(2+) exchanger proteins. This review discusses current concepts regarding the link between Na(+) entry through TRPC channels and cellular Ca(2+) signaling.

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Forefront of Na+/Ca2+ Exchanger Studies: Stoichiometry of Cardiac Na+/Ca2+ Exchanger; 3:1 or 4:1?

Cited by 19 publications

References 23 publications

Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Sodium recognition by the Na ⁺ /Ca ²⁺ exchanger in the outward-facing conformation

Na+ entry and modulation of Na+/Ca2+ exchange as a key mechanism of TRPC signaling

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Forefront of Na+/Ca2+ Exchanger Studies: Stoichiometry of Cardiac Na+/Ca2+ Exchanger; 3:1 or 4:1?

Cited by 19 publications

References 23 publications

Na+/Ca2+‐exchanger‐mediated Mn2+‐enhanced 1H2O MRI in hypoxic, perfused rat myocardium

Na+/Ca2+‐exchanger‐mediated Mn2+‐enhanced 1H2O MRI in hypoxic, perfused rat myocardium

Sodium recognition by the Na + /Ca 2+ exchanger in the outward-facing conformation

Na+ entry and modulation of Na+/Ca2+ exchange as a key mechanism of TRPC signaling

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Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Na⁺/Ca²⁺‐exchanger‐mediated Mn²⁺‐enhanced ¹H₂O MRI in hypoxic, perfused rat myocardium

Sodium recognition by the Na ⁺ /Ca ²⁺ exchanger in the outward-facing conformation