Current Structural Knowledge on the CNNM Family of Magnesium Transport Mediators

Giménez-Mascarell, Paula; González‐Recio, Irene; Fernández-Rodríguez, Carmen; Oyenarte, Iker; Müller, Dominik; Martínez‐Chantar, María Luz; Martínez-Cruz, Luis Alfonso

doi:10.3390/ijms20051135

Cited by 42 publications

(51 citation statements)

References 81 publications

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“…Among the various mechanisms of Mg 2+ sensing and transport, proteins of the Cyclin M (CNNM) family were shown to play an important role in the intracellular sensing of the Mg 2+ availability [4] [5]. The CNNM family has 4 members in mammalians, which are highly conserved but have different tissue distribution [4] [6][3] [5]. CNNM1, CNNM2 and CNNM4 have highest expression levels in brain, kidney and intestine, respectively whereas CNNM3 shows a ubiquitous expression pattern [7].…”

Section: Introductionmentioning

confidence: 99%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

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Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like protein 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

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Section: Introductionmentioning

confidence: 99%

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Zolotarov

González‐Recio

Hardy

et al. 2020

Preprint

Self Cite

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“…In the human family study, deficiency of CNNM2 has been identified in patients suffering from intellectual disability, seizures, hypomagnesemia, infertility, and altered blood pressure ( 39 ). Arjona et al reported the role of cnnm2 gene isoforms in zebrafish using a morpholino knockdown model that caused disturbed brain development, increased embryonic spontaneous contractions, weak touch-evoked escape behavior, and reduced magnesium content, indicating an impairment of renal Mg 2+ absorption ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Studies in Zebrafish Demonstrate That CNNM2 and NT5C2 Are Most Likely the Causal Genes at the Blood Pressure-Associated Locus on Human Chromosome 10q24.32

Vishnolia

Hoene

Tarhbalouti

et al. 2020

Front. Cardiovasc. Med.

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Background: Globally, high blood pressure (BP) is the most important risk factor for cardiovascular disease. Several genome-wide association studies (GWAS) have identified variants associated with BP traits at more than 535 chromosomal loci with genome-wide significance. The post-GWAS challenge is to annotate the most likely causal gene(s) at each locus. Chromosome 10q24.32 is a locus associated with BP that encompasses five genes: CYP17A1, BORCS7, AS3MT, CNNM2 , and NT5C2 and warrants investigation to determine the specific gene or genes responsible for the phenotype. Aim: To identify the most likely causal gene(s) associated with BP at the 10q24.32 locus using zebrafish as an animal model. Results: We report significantly higher blood flow, increased arterial pulse, and elevated linear velocity in zebrafish larvae with cnnm2 and nt5c2 knocked down using gene-specific splice modification transcriptional morpholinos, compared with controls. No differences in blood-flow parameters were observed after as3mt, borcs7 , or cyp17a1 knockdown. There was no effect on vessel diameter in animals with any of the four genes knocked down. At the molecular level, expression of hypertension markers ( crp and ace ) was significantly increased in cnnm2 and nt5c2 knockdown larvae. Further, the results obtained by morpholino knockdown were validated using zebrafish knockout (KO) lines with cnnm2 and nt5c2 deficiency, again resulting in higher blood flow, increased arterial pulse, and elevated linear velocity. Analysis of nt5c2a KO larvae demonstrated that lack of this gene resulted in reduced expression of cnnm2a , with reciprocal downregulation of nt5c2a in cnnm2a KO larvae. Staining of whole-blood smears from nt5c2 mutants revealed that KO of this gene might be associated with an acute lymphoblastic leukemia phenotype, consistent with literature reports. Additional experiments were designed based on previous literature on cnnm2a mutant zebrafish revealed impaired renal function, high levels of renin, and significantly increased expression of the ren gene, leading us to hypothesize that the observed elevated blood-flow parameters may be attributable to triggering of the renin–angiotensin–aldosterone signaling pathway. Conclusion: Our zebrafish data establish CNNM2 and NT5C2 as the most likely causal genes at the 10q24.32 BP locus and indicate that they trigger separate downstream mechanistic pathways.

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“…Until now, more than 600 enzymatic reactions involving magnesium have been discovered [ 14 ]. About 99% of total body magnesium is distributed between different tissues in humans, amounting to approximately 25 g of magnesium in total for adults, with the largest proportion found in bones [ 15 ]; only 1–2% of the total magnesium is located in the blood. Mg 2+ can act as an antagonist to reduce Ca 2+ signaling in endothelium [ 16 ].…”

Section: Magnesiummentioning

confidence: 99%

General Aspects of Metal Ions as Signaling Agents in Health and Disease

et al. 2020

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This review focuses on the current knowledge on the involvement of metal ions in signaling processes within the cell, in both physiological and pathological conditions. The first section is devoted to the recent discoveries on magnesium and calcium-dependent signal transduction—the most recognized signaling agents among metals. The following sections then describe signaling pathways where zinc, copper, and iron play a key role. There are many systems in which changes in intra- and extra-cellular zinc and copper concentrations have been linked to important downstream events, especially in nervous signal transduction. Iron signaling is mostly related with its homeostasis. However, it is also involved in a recently discovered type of programmed cell death, ferroptosis. The important differences in metal ion signaling, and its disease-leading alterations, are also discussed.

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Current Structural Knowledge on the CNNM Family of Magnesium Transport Mediators

Cited by 42 publications

References 81 publications

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Studies in Zebrafish Demonstrate That CNNM2 and NT5C2 Are Most Likely the Causal Genes at the Blood Pressure-Associated Locus on Human Chromosome 10q24.32

General Aspects of Metal Ions as Signaling Agents in Health and Disease

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