Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Danielsen, Andreas A.; Parker, Mark D.; Lee, Soo-Jung; Boron, Walter F.; Aalkjær, Christian; Boedtkjer, Ebbe

doi:10.1074/jbc.m113.455386

Cited by 32 publications

(21 citation statements)

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“…7), led us to postulate that the genotypic effect was independent of calcineurin activity. Furthermore, the genotypic effect was observed in conditions with lower intracellular [Ca 2+ ], where calcineurin is less likely to play a role (30). To assess this hypothesis, primary VSMCs were assessed for Na + - and CO 2 /

{HCO}_{3}^{-}

-dependent, DMA-insensitive pH i recovery rate following

{NH}_{4}^{+}

-prepulse-induced intracellular acidosis while being exposed to 10 µM of the calcineurin inhibitor FK506 (or equivolume DMSO vehicle).…”

Section: Resultsmentioning

confidence: 99%

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Boedtkjer

Witkowska

et al. 2017

Hum. Mol. Genet.

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Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3− co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.

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{HCO}_{3}^{-}

-dependent, DMA-insensitive pH i recovery rate following

{NH}_{4}^{+}

-prepulse-induced intracellular acidosis while being exposed to 10 µM of the calcineurin inhibitor FK506 (or equivolume DMSO vehicle).…”

Section: Resultsmentioning

confidence: 99%

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Boedtkjer

Witkowska

et al. 2017

Hum. Mol. Genet.

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“…NBCn1 has also been shown to interact physically and functionally with calcineurin Aβ (84). This interaction involves a calcineurin binding motif PTVVIH in cassette II in NBCn1.…”

Section: The Postcloning Eramentioning

confidence: 99%

“…This interaction involves a calcineurin binding motif PTVVIH in cassette II in NBCn1. Calcineurin is required for Ca 2+ -induced activation of NBCn1 and inhibition of calcineurin augments intracellular acidification during rat mesenteric artery contraction (84). Since cassette II is predominantly expressed in smooth, cardiac and skeletal muscle tissues (74) this observation is an important step towards understanding the functional implication of different splice variants and a mechanism of tissue specific regulation of NBCn1.…”

Section: The Postcloning Eramentioning

confidence: 99%

Cation‐Coupled Bicarbonate Transporters

Aalkjær

Boedtkjer

Choi

et al. 2014

Comprehensive Physiology

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Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family.

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“…The regulation of NBC activity during artery contraction is associated with pH control ( Table 1). The calcineurin A signaling pathway interacts with NBCn1, but not NHE, and modulates the NBC activity in VSMCs [109]. NBCn1-null mice were observed to exhibit attenuated myogenic tone in the presence of N-nitro-L-arginine methyl ester (L-NAME), and reduction in rhythmic contractile pattern compared to the wild type [110].…”

Section: Vascular Smooth Muscle Systemmentioning

confidence: 99%

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

Lee¹,

Hong²

2020

IJMS

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The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved in the mechanism of bicarbonate movement and consist of complex of bicarbonate transport systems including bicarbonate transporters. This review focused on the convergent regulation of ion homeostasis through various ion transporters including bicarbonate transporters, their regulatory enzymes, such as carbonic anhydrases, pH regulatory role, and the expression pattern of ion transporters in non-secretory systems throughout the body. Understanding the correlation between these systems will be helpful in order to obtain new insights and design potential therapeutic strategies for the treatment of pH-related disorders. In this review, we have discussed the broad prospects and challenges that remain in elucidation of bicarbonate-transport-related biological and developmental systems.

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Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Cited by 32 publications

References 50 publications

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Cation‐Coupled Bicarbonate Transporters

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

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Splice Cassette II of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Interacts with Calcineurin A

Cited by 32 publications

References 50 publications

Increased NBCn1 expression, Na + /HCO 3 - co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Increased NBCn1 expression, Na + /HCO 3 - co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Cation‐Coupled Bicarbonate Transporters

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

Contact Info

Product

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About

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension

Increased NBCn1 expression, Na ⁺ /HCO ₃ ^- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension