Structure–Function Relationships of the NCKX2 Na+/Ca2+‐K+ Exchanger

Shibukawa, Yoshiyuki; Kang, Kyung-In; Kinjo, Tashi G.; Szerencsei, Robert T.; Altimimi, Haider F.; Pratikhya, P.; Winkfein, Robert J.; Schnetkamp, Paul P. M.

doi:10.1196/annals.1387.054

Cited by 8 publications

(5 citation statements)

References 41 publications

(83 reference statements)

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“…[80] The 111 Thr/Ala polymorphism is thought to occur in the trans-membrane domain. [81] Over-expression of the 111 Thr allele (found predominantly in Europeans with light skin) experimentally reduces the exchange rate of Ca 2+ which is hypothesized to subsequently influence the Na + gradient and influence downstream function of melanosomal and plasma membrane Na + /H + exchangers and ultimately changes the pH within the melanosome. [69, 80] Conversely, calcitriol has not been found to upregulate SLC24A5 expression, although this has not been investigated in melanocytes or keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

Genetic ancestry, skin reflectance and pigmentation genotypes in association with serum vitamin D metabolite balance

Wilson

Roff

Dai

et al. 2011

Hormone Molecular Biology and Clinical Investigation

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Background Lower serum vitamin D (25(OH)D) among individuals with African ancestry is attributed primarily to skin pigmentation. However, the influence of genetic polymorphisms controlling for skin melanin content has not been investigated. Therefore, we investigated differences in non-summer serum vitamin D metabolites according to self-reported race, genetic ancestry, skin reflectance and key pigmentation genes (SLC45A2 and SLC24A5). Materials and Methods Healthy individuals reporting at least half African American or half European American heritage were frequency matched to one another on age (+/− 2 years) and sex. 176 autosomal ancestry informative markers were used to estimate genetic ancestry. Melanin index was measured by reflectance spectrometry. Serum vitamin D metabolites (25(OH)D3, 25(OH)D2 and 24,25(OH)2D3) were determined by high performance liquid chromatography (HPLC) tandem mass spectrometry. Percent 24,25(OH)2D3 was calculated as a percent of the parent metabolite (25(OH)D3). Stepwise and backward selection regression models were used to identify leading covariates. Results Fifty African Americans and 50 European Americans participated in the study. Compared with SLC24A5 111Thr homozygotes, individuals with the SLC24A5 111Thr/Ala and 111Ala/Ala genotypes had respectively lower levels of 25(OH)D3 (23.0 and 23.8 nmol/L lower, p-dominant=0.007), and percent 24,25(OH)2D3 (4.1 and 5.2 percent lower, p-dominant=0.003), controlling for tanning bed use, vitamin D/fish oil supplement intake, race/ethnicity, and genetic ancestry. Results were similar with melanin index adjustment, and were not confounded by glucocorticoid, oral contraceptive, or statin use. Conclusions The SLC24A5 111Ala allele was associated with lower serum vitamin 25(OH)D3 and lower percent 24,25(OH)2D3, independently from melanin index and West African genetic ancestry.

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Section: Discussionmentioning

confidence: 99%

Genetic ancestry, skin reflectance and pigmentation genotypes in association with serum vitamin D metabolite balance

Wilson

Roff

Dai

et al. 2011

Hormone Molecular Biology and Clinical Investigation

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“…These complexes are in turn associated with the major calcium extrusion protein of outer segments, the Na + /Ca 2+ ,K + exchanger (Bauer, 2002, Schnetkamp, 1989. Although progress has been made in establishing the stoichiometry of the participants in this complex, and in the functional roles of specific domains and residues within them (Bradley, et al, 2005, Kaupp & Seifert, 2002, Matulef & Zagotta, 2003, Shibukawa, et al, 2007, little is known about their structural arrangement. Electron microscopy and single-particle analysis have been used to determine a low resolution structure of the CNG channel (Higgins, et al, 2002), and there is a high resolution structure of a cyclic nucleotide-binding domain similar to that of the photoreceptor CNG channel .…”

Section: Plasma Membrane Complexesmentioning

confidence: 99%

Signal transducing membrane complexes of photoreceptor outer segments

Wensel¹

2008

Vision Research

105

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Signal transduction in outer segments of vertebrate photoreceptors is mediated by a series of reactions among multiple polypeptides that form protein-protein complexes within or on the surface of the disk and plasma membranes. The individual components in the activation reactions include the photon receptor rhodopsin and the products of its absorption of light, the three subunits of the G protein, transducin, the four subunits of the cGMP phosphodiesterase, PDE6 and the four subunits of the cGMP-gated cation channel. Recovery involves membrane complexes with additional polypeptides including the Na(+)/Ca(2+), K(+) exchanger, NCKX2, rhodopsin kinases RK1 and RK7, arrestin, guanylate cyclases, guanylate cyclase activating proteins, GCAP1 and GCAP2, and the GTPase accelerating complex of RGS9-1, G(beta5L), and membrane anchor R9AP. Modes of membrane binding by these polypeptides include transmembrane helices, fatty acyl or isoprenyl modifications, polar interactions with lipid head groups, non-polar interactions of hydrophobic side chains with lipid hydrocarbon phase, and both polar and non-polar protein-protein interactions. In the course of signal transduction, complexes among these polypeptides form and dissociate, and undergo structural rearrangements that are coupled to their interactions with and catalysis of reactions by small molecules and ions, including guanine nucleotides, ATP, Ca(2+), Mg(2+), and lipids. The substantial progress that has been made in understanding the composition and function of these complexes is reviewed, along with the more preliminary state of our understanding of the structures of these complexes and the challenges and opportunities that present themselves for deepening our understanding of these complexes, and how they work together to convert a light signal into an electrical signal.

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“…The latter is a bidirectional transporter that catalyzes the electrogenic exchange of 3 Na + for 1 Ca 2+ , depending on the electrochemical gradient of the substrate ions [1–4]. These exchangers play an important role in the regulation of intracellular free Ca 2+ concentration ([Ca 2+ ]i) in both excitable and non-excitable cells and pump Ca 2+ out of cells by means of the Na + concentration gradient across the cell membrane [2–9]. Mammalian NCXs comprising NCX1, NCX2, and NCX3 constitute the multigene superfamily SLC8 encoded by three separate genes [1,3,10].…”

Section: Introductionmentioning

confidence: 99%

Sodium-Calcium Exchangers in Rat Trigeminal Ganglion Neurons

et al. 2013

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BackgroundNoxious stimulation and nerve injury induce an increase in intracellular Ca2+ concentration ([Ca2+]i) via various receptors or ionic channels. While an increase in [Ca2+]i excites neurons, [Ca2+]i overload elicits cytotoxicity, resulting in cell death. Intracellular Ca2+ is essential for many signal transduction mechanisms, and its level is precisely regulated by the Ca2+ extrusion system in the plasma membrane, which includes the Na+-Ca2+ exchanger (NCX). It has been demonstrated that Ca2+-ATPase is the primary mechanism for removing [Ca2+]i following excitatory activity in trigeminal ganglion (TG) neurons; however, the role of NCXs in this process has yet to be clarified. The goal of this study was to examine the expression/localization of NCXs in TG neurons and to evaluate their functional properties.ResultsNCX isoforms (NCX1, NCX2, and NCX3) were expressed in primary cultured rat TG neurons. All the NCX isoforms were also expressed in A-, peptidergic C-, and non-peptidergic C-neurons, and located not only in the somata, dendrites, axons and perinuclear region, but also in axons innervating the dental pulp. Reverse NCX activity was clearly observed in TG neurons. The inactivation kinetics of voltage-dependent Na+ channels were prolonged by NCX inhibitors when [Ca2+]i in TG neurons was elevated beyond physiological levels.ConclusionsOur results suggest that NCXs in TG neurons play an important role in regulating Ca2+-homeostasis and somatosensory information processing by functionally coupling with voltage-dependent Na+ channels.

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Structure–Function Relationships of the NCKX2 Na⁺/Ca²⁺‐K⁺ Exchanger

Cited by 8 publications

References 41 publications

Genetic ancestry, skin reflectance and pigmentation genotypes in association with serum vitamin D metabolite balance

Genetic ancestry, skin reflectance and pigmentation genotypes in association with serum vitamin D metabolite balance

Signal transducing membrane complexes of photoreceptor outer segments

Sodium-Calcium Exchangers in Rat Trigeminal Ganglion Neurons

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