Interaction of the Ca<sup>2+</sup>-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function

Huang, Changcheng; Sinđić, Aleksandra; Hill, Ceredwyn E.; Hujer, Kristine M.; Chan, Kim W.; Sassen, Martin; Wu, Zhenzhen; Kurachi, Yoshihisa; Nielsén, Sören; Romero, Michael F.; Miller, R. Tyler

doi:10.1152/ajprenal.00269.2006

Cited by 79 publications

(82 citation statements)

References 46 publications

(64 reference statements)

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“…Many members of the Kir (inwardly-rectifying K ϩ channel) family of K ϩ channels are regulated by G protein-coupled receptors that alter the P o over short time frames through phosphatidylinositol bisphosphate metabolism or protein-protein interactions (18,19). We found that co-expression of the CaR WT and Kir4.1 in Xenopus oocytes led to reduced whole cell currents, whereas the nonfunctional mutant CaR R795W had no effect (10). Inactivation of Kir4.1 by the CaR is not mediated by short term changes in receptor signaling, as changes in Ca 2ϩ over the range 0.1-5 mM or addition of Gdϩ (CaR agonist), had no effect on channel activity (10).…”

Section: Control Of Kir41 Cell Surface Abundance By Car-mentioning

confidence: 80%

“…We found that co-expression of the CaR WT and Kir4.1 in Xenopus oocytes led to reduced whole cell currents, whereas the nonfunctional mutant CaR R795W had no effect (10). Inactivation of Kir4.1 by the CaR is not mediated by short term changes in receptor signaling, as changes in Ca 2ϩ over the range 0.1-5 mM or addition of Gdϩ (CaR agonist), had no effect on channel activity (10). Pursuing long term receptor effects on channel activity in this study, we investigated the ability of the CaR WT and CaR mutants with a range of signaling activities to affect Kir4.1 cell surface expression using cell surface biotinylation and current density with the whole cell patch technique in HEK-293 cells.…”

Section: Control Of Kir41 Cell Surface Abundance By Car-mentioning

confidence: 80%

“…The monoclonal anti-CaR and anti-HA antibodies and HEK-293 cells that stably overexpress the wild-type CaR were described previously (10,11). G418 sulfate and cell culture reagents were purchased from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

“…We found that CaR WT inactivates Kir4.1, whereas the nonfunctional mutant CaR R795W has no effect. The activity of Kir4.1 is not affected by short term changes in Ca 2ϩ o , suggesting initially that inactivation of Kir4.1 is a relatively long term effect of CaR WT signaling that could involve processes such as protein trafficking (10). This mechanism has three notable features.…”

mentioning

confidence: 99%

“…The hypocalciuric, hypomagnesemic variant of Bartter syndrome, Gitelman syndrome, is due to loss of function mutations of the thiazide-sensitive NaCl co-transporter (6). The recently described SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) or EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome is caused by loss of function mutations in Kir4.1 (KCNJ10), an inwardly rectifying K ϩ channel that is expressed in the basolateral membrane of the distal nephron (7)(8)(9)(10). Presumably, reduced activity of Kir4.1 impairs recycling of K ϩ for the Na,K-ATPase reducing net transepithelial Na 2ϩ transport.…”

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confidence: 99%

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Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Kuy

Huang

Ding³

et al. 2011

Journal of Biological Chemistry

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The Ca 2؉ -sensing receptor (CaR) regulates salt and water transport in the kidney as demonstrated by the association of gain of function CaR mutations with a Bartter syndrome-like, salt-wasting phenotype, but the precise mechanism for this effect is not fully established. We found previously that the CaR interacts with and inactivates an inwardly rectifying K ؉ channel, Kir4.1, which is expressed in the distal nephron that contributes to the basolateral K ؉ conductance, and in which loss of function mutations are associated with a complex phenotype that includes renal salt wasting. We now find that CaR inactivates Kir4.1 by reducing its cell surface expression. Mutant CaRs reduced Kir4.1 cell surface expression and current density in HEK-293 cells in proportion to their signaling activity. Mutant, activated G␣ q reduced cell surface expression and current density of Kir4.1, and these effects were blocked by RGS4, a protein that blocks signaling via G␣ i and G␣ q . Other ␣ subunits had insignificant effects. Knockdown of caveolin-1 blocked the effect of G␣ q on Kir4.1, whereas knockdown of the clathrin heavy chain had no effect. CaR had no comparable effect on the renal outer medullary K ؉ channel, an apical membrane distal nephron K ؉ channel that is internalized by clathrin-coated vesicles. Co-immunoprecipitation studies showed that the CaR and Kir4.1 physically associate with caveolin-1 in HEK cells and in kidney extracts. Thus, the CaR decreases cell surface expression of Kir4.1 channels via a mechanism that involves G␣ q and caveolin. These results provide a novel molecular basis for the inhibition of renal NaCl transport by the CaR.Sodium transport in the distal nephron determines body volume and blood pressure as demonstrated by the fact that mutations in genes expressed in this region of the kidney can cause either salt retention and high blood pressure or salt wasting and low blood pressure (1). A number of genetically distinct syndromes caused by abnormalities of transport proteins expressed in the distal nephron lead to phenotypes characterized by salt wasting. Bartter syndrome can result from loss of function mutations of the NaK 2 Cl co-transporter (NKCC2), 2 the renal outer medullary K ϩ channel (ROMK or Kir1.1), or the ClC-Kb (basolateral Cl Ϫ channel). A variant also characterized by sensorineural deafness is caused by loss of function mutations in an accessory protein for ClC-Kb, barttin (Bartter syndrome neuraosensory deafness or BSND) (1-5). The hypocalciuric, hypomagnesemic variant of Bartter syndrome, Gitelman syndrome, is due to loss of function mutations of the thiazide-sensitive NaCl co-transporter (6). The recently described SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) or EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome is caused by loss of function mutations in Kir4.1 (KCNJ10), an inwardly rectifying K ϩ channel that is expressed in the basolateral membrane of the distal nephron (7-10). Presumably, reduced acti...

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Section: Control Of Kir41 Cell Surface Abundance By Car-mentioning

confidence: 80%

Section: Control Of Kir41 Cell Surface Abundance By Car-mentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Kuy

Huang

Ding³

et al. 2011

Journal of Biological Chemistry

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Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Tian,

Andrews,

Yan

et al. 2024

Chronic Diseases and Translational Medicine

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Calcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

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Distal Convoluted Tubule

McCormick

Ellison

2014

Comprehensive Physiology

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Interaction of the Ca²⁺-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function

Cited by 79 publications

References 46 publications

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Distal Convoluted Tubule

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Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function

Cited by 79 publications

References 46 publications

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Distal Convoluted Tubule

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Interaction of the Ca²⁺-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function