A novel homozygous mutation (p.N958K) of SLC12A3 in Gitelman syndrome is associated with endoplasmic reticulum stress

Tang, Wei; Huang, Xiaolun; Liu, Y; Lv, Quan-Zhen; Li, T; Song, Yu; Zhang, Xue Song; Chen, X; Shi, Yongquan

doi:10.1007/s40618-020-01329-y

Cited by 4 publications

(3 citation statements)

References 40 publications

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“…Because of the critical roles of NCC in maintaining the homeostasis of sodium, many disease mutations of NCC associated with Gitelman syndrome have been reported (41,(47)(48)(49)(50)(51). We mapped these disease mutations into the NCC structure by categorizing them into several groups based on their locations or functions in NCC (fig.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 Å for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC.

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Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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“…↓ Thiazide-sensitive Na uptake, N958K: impaired Na transport & ↑ endoplasmic reticulum stress activation, Q1030A: membrane localization impaired. ↓ Thiazide-sensitive Na uptake [ 49 , 54 , 56 , 57 , 58 ] N640S, T649M, L892P, P947S Salt-losing tubulopathy [ 59 ] (r)G777E Low blood pressure ↓ Na uptake activity, No change in membrane expression [ 60 ] A728T, R904Q, R919C Hypertension R919C: membrane expression not affected. ↑ Na uptake [ 49 ] NKCC1 H186AfsX17 NT NDD &/or cochleovestibular defect ↓ K transport activity [ 63 ] Y199C SCZ ↑ Cl-dependent & bumetanide-sensitive activity even in hypotonicity [ 64 ] A327V, N376I, A379L, R410Q TM NDD &/or cochleovestibular defect ↓ K transport activity [ 63 ] W892X, E980K CT NDD &/or cochleovestibular defect ↓ K transport activity [ 63 ] E979K, D981Y, P988T Hearing loss [ 62 ] V1026FfsXX multisystem impairment [ 12 ] NKCC2 …”

Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

“…The mutations linked to GS are predominately located in the ion-translocation pathway, the EC domain, the TM–TM and TM–cytosol interfaces, and the NT and CT domains, likely affecting NCC folding and stability [ 20 , 55 , 56 ]. In vitro functional characterization of NCC missense mutations associated with GS revealed defective NCC plasma membrane expression, localization, and activity [ 57 , 58 ]. Interestingly, some NCC mutations associated with GS are also associated with salt-losing tubulopathy [ 59 ].…”

Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

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Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies. Cation-coupled chloride cotransporters (CCCs): from structure to function and modulationCCCs are proteins (~130 kDa) of the subfamily of solute carrier transporters (see Glossary) 12 (SLC12) that modulate transport of sodium and/or potassium cations (Na + , K + ) and chloride anions (Cl -) across the cell membrane (Figure 1A). In humans, there are seven known electroneutral CCCs: the Na + -Clcotransporter NCC, the Na + -K + -Clcotransporters NKCC1 and NKCC2, and the K + -Clcotransporters KCC1, KCC2, KCC3, and KCC4 (Figure 1B) [1]. NCC and NKCC2 are expressed predominantly in the kidney [2]. NKCC1, KCC1, KCC3, and KCC4 are expressed throughout the body. KCC2 is expressed specifically in neurons [3]. CCCs are involved in physiological processes, including salt absorption and secretion, cell volume regulation, and intracellular Clconcentration setting [1,4]. As such, CCCs are primarily implicated in blood pressure regulation, cardiovascular and brain physiopathology, and diuresis, and are also associated with hearing and tumoral diseases (Figure 1C,D). Structure-function relationshipsCCCs mainly form homodimers, although multimeric states have been described in functional assays for N(K)CCs and KCCs [5][6][7]. Monomers for each of the CCC family members are characterized by a well-conserved transmembrane (TM) domain formed by 12 TM helices, one N-glycosylated extracellular (EC) domain, and, on the cytosolic side, the amino-terminal (NT) and the large carboxy-terminal (CT) domains (Figure 1A). All SLC12-CCC members share the same TM protein fold of the leucine transporter (LeuT [8], Box 1). The EC domain is characterized by a connecting loop between TM7 and TM8 in Na + -dependent CCCs, whereas Na + -independent CCCs have a longer loop between TM5 and TM6. The NT and EC domains are variable in amino acid length, much shorter than the CT domain, and poorly conserved among the CCC members. The EC domains contain glycosylation sites, whereas the intracellular domains contain phosphorylation sites to modulate CCC function (Figure 1A) [9]. Molecular heterogeneity is also provided by multiple CCC isoforms, generated by alternative splicing and alternative promote...

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