Na+/Ca2+-K+Exchangers (NCKX):Functional Properties and Physiological Roles

Altimimi, Haider F.; Schnetkamp, Paul P. M.

doi:10.4161/chan.4366

Cited by 53 publications

(42 citation statements)

References 52 publications

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“…Na + /Ca 2+ exchanger proteins (NCXs) are important for maintaining cardiac contractility in cardiac muscle and for neuronal transmission in brain (3). Dysfunction of Na + /Ca 2+ -K + exchangers (NCKXs) impairs skin and retinal pigmentation, as well as synaptic plasticity (4).…”

Section: Camentioning

confidence: 99%

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation

Wu¹,

Shu²,

Waltersperger

et al. 2013

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

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CaCAs are integral membrane proteins containing 10-11 predicted transmembrane helices (TMs) (1) (SI Appendix, Fig. S1). Despite the divergence in cation driving force, the superfamily is defined by the presence of two highly conserved α-repeat motifs in TMs 2-3 (α-1) and TMs 7-8 (α-2). The importance of these conserved motifs for Ca 2+ /cation exchange has been well documented in all characterized CaCA proteins (8-10), implying the conservation of the Ca 2+ /cation translocation mechanism in the CaCA superfamily. Recently, Liao et al. reported the crystal structure of the NCX_Mj protein (6). The structure shows a large cavity opening on the periplasmic surface (outward-facing conformation) with both Ca 2+ and Na + bound at the α-repeat regions, suggesting the following hypotheses: (i) a substrate alternating access mechanism in which Ca 2+ and the counter transported cation access the ion-binding sites from each side of the membrane surface; and (ii) transition between outward-facing and inward-facing conformations is required to achieve Ca 2+ /cation exchange. Although the structure of the outward-facing conformation of NCX_Mj is available, structural evidence for the conformational change essential for alternating substrate access has not yet been obtained for any CaCA member. In addition, how the CaCA superfamily proteins modify their Ca 2+ -translocation pathways to use the different cation-gradient driving forces, H + vs. Na + , remains a fundamental and interesting question.To address these important questions, here, we report the crystal structure of an inward-facing conformation of the YfkE protein. This structure, together with protein kinetic analysis, not only provides an important structural characterization of the mechanism of Ca 2+ efflux across the cell membrane but also sheds light on the different modes of energy coupling used by members of the CaCA protein superfamily. Results Ca 2+-Transport Specificity and Structural Determination of YfkE. YfkE catalyzes a H+ -coupled Ca 2+ influx in everted vesicles (SI Appendix, Fig. S2A This article is a PNAS Direct Submission.Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4KJR and 4KJS).

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Section: Camentioning

confidence: 99%

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation

Wu¹,

Shu²,

Waltersperger

et al. 2013

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

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“…A second species of the model that regulates the intracellular levels of Ca 2+ is NCKX, which is a bidirectional transporter that exchange Na + /Ca 2+ +K + with stoichiometry of 4 Na + :1 Ca 2+ + 1 K + [133], [134]. The main function of NCKX exchangers is to extrude Ca 2+ from the cytoplasm to the exterior of the cell, a process that is observed in the OSNs [16], [22].…”

Section: Modelmentioning

confidence: 99%

Mechanisms of Regulation of Olfactory Transduction and Adaptation in the Olfactory Cilium

2014

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Olfactory adaptation is a fundamental process for the functioning of the olfactory system, but the underlying mechanisms regulating its occurrence in intact olfactory sensory neurons (OSNs) are not fully understood. In this work, we have combined stochastic computational modeling and a systematic pharmacological study of different signaling pathways to investigate their impact during short-term adaptation (STA). We used odorant stimulation and electroolfactogram (EOG) recordings of the olfactory epithelium treated with pharmacological blockers to study the molecular mechanisms regulating the occurrence of adaptation in OSNs. EOG responses to paired-pulses of odorants showed that inhibition of phosphodiesterases (PDEs) and phosphatases enhanced the levels of STA in the olfactory epithelium, and this effect was mimicked by blocking vesicle exocytosis and reduced by blocking cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and vesicle endocytosis. These results suggest that G-coupled receptors (GPCRs) cycling is involved with the occurrence of STA. To gain insights on the dynamical aspects of this process, we developed a stochastic computational model. The model consists of the olfactory transduction currents mediated by the cyclic nucleotide gated (CNG) channels and calcium ion (Ca2+)-activated chloride (CAC) channels, and the dynamics of their respective ligands, cAMP and Ca2+, and it simulates the EOG results obtained under different experimental conditions through changes in the amplitude and duration of cAMP and Ca2+ response, two second messengers implicated with STA occurrence. The model reproduced the experimental data for each pharmacological treatment and provided a mechanistic explanation for the action of GPCR cycling in the levels of second messengers modulating the levels of STA. All together, these experimental and theoretical results indicate the existence of a mechanism of regulation of STA by signaling pathways that control GPCR cycling and tune the levels of second messengers in OSNs, and not only by CNG channel desensitization as previously thought.

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“…In the dark, the influx of calcium through cGMP-gated transduction channels is matched by its extrusion via rod-or cone-specific Na ϩ /(Ca 2ϩ , K ϩ ) exchangers (6). Activation of the phototransduction cascade by light results in the closure of cGMP channels and a block of the influx of calcium.…”

mentioning

confidence: 99%

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Sakurai

Chen

Khani

et al. 2015

Journal of Biological Chemistry

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Background: Calcium-mediated feedback to phototransduction is critical for modulating cone responses under different lighting conditions. Results: The calcium-binding protein recoverin potentiates dim light sensitivity, whereas increasing expression of its target, GRK1, delays response shutoff in cones. Conclusion: Recoverin and GRK1 levels modulate cone phototransduction. Significance: Cone pigment inactivation regulates cone responses in dim light but not in bright light.

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Na⁺/Ca²⁺-K⁺Exchangers (NCKX):Functional Properties and Physiological Roles

Cited by 53 publications

References 52 publications

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation

Mechanisms of Regulation of Olfactory Transduction and Adaptation in the Olfactory Cilium

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

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Na+/Ca2+-K+Exchangers (NCKX):Functional Properties and Physiological Roles

Cited by 53 publications

References 52 publications

Crystal structure of Ca 2+ /H + antiporter protein YfkE reveals the mechanisms of Ca 2+ efflux and its pH regulation

Crystal structure of Ca 2+ /H + antiporter protein YfkE reveals the mechanisms of Ca 2+ efflux and its pH regulation

Mechanisms of Regulation of Olfactory Transduction and Adaptation in the Olfactory Cilium

Regulation of Mammalian Cone Phototransduction by Recoverin and Rhodopsin Kinase

Contact Info

Product

Resources

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Na⁺/Ca²⁺-K⁺Exchangers (NCKX):Functional Properties and Physiological Roles

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation

Crystal structure of Ca ²⁺ /H ⁺ antiporter protein YfkE reveals the mechanisms of Ca ²⁺ efflux and its pH regulation