The Na+/H+ exchanger isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins. Identification and characterization of calmodulin-binding sites.

Bertrand, Bénédicte; Wakabayashi, Shigeo; Ikeda, Toshitaro; Pouysségur, Jacques; Shigekawa, Munekazu

doi:10.1016/s0021-9258(17)36887-4

Cited by 288 publications

(56 citation statements)

References 44 publications

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“…It, therefore, seems unlikely that the C‐terminal tail in NHE9 interacts tightly with the transporter module in the absence of binding partners. Nevertheless, since the regulatory domain in NHE9 lacks the Ca 2+ ‐CaM‐binding motifs (Bertrand et al , 1994), we cannot assess if this auto‐inhibitory mechanism occurs in NHE1 and other isoforms harbouring Ca 2+ ‐CaM‐binding sites. In addition to CTD, the length of the N‐terminus also varies, from 23 residues upstream of TM1 in NHE9, to 84 amino acids upstream of the modelled TM1 in NHE1 (Fig EV1).…”

Section: Discussionmentioning

confidence: 98%

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

et al. 2020

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Na+/H+ exchangers (NHEs) are ancient membrane‐bound nanomachines that work to regulate intracellular pH, sodium levels and cell volume. NHE activities contribute to the control of the cell cycle, cell proliferation, cell migration and vesicle trafficking. NHE dysfunction has been linked to many diseases, and they are targets of pharmaceutical drugs. Despite their fundamental importance to cell homeostasis and human physiology, structural information for the mammalian NHE was lacking. Here, we report the cryogenic electron microscopy structure of NHE isoform 9 (SLC9A9) from Equus caballus at 3.2 Å resolution, an endosomal isoform highly expressed in the brain and associated with autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders. Despite low sequence identity, the NHE9 architecture and ion‐binding site are remarkably similar to distantly related bacterial Na+/H+ antiporters with 13 transmembrane segments. Collectively, we reveal the conserved architecture of the NHE ion‐binding site, their elevator‐like structural transitions, the functional implications of autism disease mutations and the role of phosphoinositide lipids to promote homodimerization that, together, have important physiological ramifications.

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Section: Discussionmentioning

confidence: 98%

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

et al. 2020

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“…The rise in intracellular Ca 2+ as well as the intracellular accumulation of H + generated by NOX initiate H + extrusion, via H v 1 and the sodium-proton exchanger 1 (NHE1) [10,[74][75][76][77]. H v 1 is a voltage-dependent H + channel activated by cellular depolarization [64,72,78].…”

Section: Electron and Proton Fluxes Mediate Depolarization And Intracmentioning

confidence: 99%

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

Messerer

Schmidt

Frick

et al. 2021

IJMS

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Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion–water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis.

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“…The PKA consensus sites are identical to two of four such sites found in NHE, whereas hNHE1 lacks PKA consensus sites. In contrast, in the region (amino acids 636-656 in hNHE1, 624-644 in paNHE1) identified in hNHE1 as a high-affinity calmodulin-binding region, 19 paNHE1 is more similar to hNHE1 despite its overall greater homology to NHE. 28 Interestingly, the calmodulin-binding region has been implicated in shrinkage-mediated activation of hNHE1, 19 pointing to the possibility that these sequence differences may underlie the markedly different shrinkage-sensitivity of paNHE1 and NHE.…”

Section: The Panhe1 Protein: Sequence Topology and Localizationmentioning

confidence: 85%

“…3 For instance, NHE1 is directly phosphor-ylated in response to growth factor activation, but there is no clear picture as to the extent this phosphorylation is necessary for the ensuing activation of NHE1. 3 The mammalian NHE1 has been shown to bind directly to a wide range of proteins and other accessory factors which are themselves regulated by phosphorylation-dependent processes includ-ing calmodulin, 19 the band 4/ezrin/radixin/moesin (FERM) proteins 20 and via them, F-actin, the phospholipid phosphatidyl inositol 4,5 bisphosphate (PtdIns(4,5)P 2 ), 21 and car-bonic anhydrase II. 22 Thus, evidence is accumulating that NHE1 is part of a tightly regulated multi-protein complex and stimuli affecting NHE1 activity could act either on NHE1 itself or on an associated protein.…”

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confidence: 99%

A Novel NHE1 from Red Blood Cells of the Winter Flounder

Pedersen¹

Cell Volume and Signaling

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The ubiquitously expressed plasma membrane Na + /H + exchanger, NHE1, plays a major role in the regulatory volume increase (RVI) process after cell shrinkage. NHE1 is also activated by acidification, stimulation of receptors for a wide range of hormones and growth factors, and inhibition of Ser/Thr protein phosphatases by DNA tumor viruses or compounds such as okadaic acid and calyculin A. [1][2][3][4][5][6] Consequently, NHE1 serves important physiological functions not just as a mechanism of pH-and cell volume homeostasis but also as a signal transducer which converts growth hormone signals into pH-and/or cell volume changes away from the steady state set point. In turn, these changes can modulate cell migration, 7 cell cycle control, 8 and programmed cell death. 9 In teleost red blood cells (RBCs), a major physiological function of NHE1 is the modulation of hemoglobin (Hb) O 2 affinity. Exposure of fish to hypoxia or exercise stress elicits release of catecholamines which act on -adrenergic receptors on the RBCs, resulting in increased cellular cAMP levels, and NHE1 activation. In trout, the receptor involved was recently identified as a novel, isoproterenol-sensitive 3 isoform. 10 Both the ensuing intracellular alkalinization and cell swelling contribute to increase the O 2 affinity of Hb, the former via the Bohr/Root effects, the latter as a result of the dilution of [Hb]. 11 Reflecting this special function, NHE1s from teleost RBCs tend to be robustly activated by cAMP but display little or no activity in response to osmotic shrinkage, especially at physiological P O2 . 12,13 Given the pleiotropic roles of NHE1, it is perhaps not surprising that excessive NHE1 activity has been found to play a major role in a number of important pathological states. One example is that of hypoxia/ischemia-induced cell damage. During ischemia/ reperfusion in the heart, activation of NHE1 increases [Na + ] i , resulting in reversal of Na + /Ca 2+ exchange and Ca 2+ overload. 14 NHE1 is also activated during brain hypoxia/

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The Na+/H+ exchanger isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins. Identification and characterization of calmodulin-binding sites.

Cited by 288 publications

References 44 publications

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9

Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis

A Novel NHE1 from Red Blood Cells of the Winter Flounder

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