Ae4 (Slc4a9) Anion Exchanger Drives Cl− Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells

Peña-Münzenmayer, Gaspar; Catalán, Marcelo A.; Kondo, Yusuke; Jaramillo, Yasna; Liu, Frances; Shull, Gary E.; Melvin, James E.

doi:10.1074/jbc.m114.612895

Cited by 33 publications

(68 citation statements)

References 58 publications

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“…SLC4A9 is restricted to the basolateral membrane of acinar cells, where it participates in saliva secretion (86, 87) ( Figure 4B). SLC4A9 knockout mice displayed a 35% reduction in saliva secreted from the submandibular gland (86). This suggests that loss of SLC4A9 in cetaceans could contribute to a reduction of saliva secretion, which is in agreement with morphological observations that salivary glands are absent or atrophied in cetaceans (88,89).…”

Section: Loss Of An Ion Transporter Gene and Feeding In An Aquatic Ensupporting

confidence: 84%

“…SLC4A9 encodes an ion transporter. 1) In the submandibular salivary gland, SLC4A9 participates in creating a transepithelial chloride anion flux into the acinar lumen, together with another transporter SLC12A2 and chloride channels (86). 2) This first evokes a passive movement of cations across the tight junctions into the acinar lumen.…”

Section: Data Availabilitymentioning

confidence: 99%

“…3) The resulting osmotic gradient induces a flow of water, which constitutes fluid secretion into the acinar lumen, the initial site of saliva secretion (140). SLC4A9 knockout in mice leads to a 35% reduction in saliva secretion (86). The remaining saliva secretion potential in SLC4A9 knockout mice is maintained by SLC12A2 (86).…”

Section: Figuresmentioning

confidence: 99%

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Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Huelsmann

Hecker

Springer

et al. 2019

Preprint

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The transition from land to water in whales and dolphins (cetaceans) was accompanied by remarkable anatomical, physiological and behavioral adaptations. To better understand the genomic changes that occurred during this transition, we systematically screened for protein-coding genes that were inactivated in the ancestral cetacean lineage. We discovered genes whose loss is likely beneficial for cetaceans by reducing the risk of thrombus formation during diving (F12, KLKB1), improving the fidelity of oxidative DNA damage repair (POLM), and protecting from oxidative stress-induced lung inflammation (MAP3K19). Additional gene losses may reflect other diving-related adaptations, such as enhanced vasoconstriction during the diving response (mediated by SLC6A18) and altered pulmonary surfactant composition (SEC14L3), while loss of SLC4A9 relates to a reduced need for saliva in aquatic environments. Finally, the complete loss of melatonin synthesis and receptor genes (AANAT, ASMT, MTNR1A/B) may have been a precondition for the evolution of unihemispheric sleep. Our findings suggest that some genes lost in the ancestral cetacean lineage may have been involved in adapting to a fully-aquatic lifestyle.

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Section: Loss Of An Ion Transporter Gene and Feeding In An Aquatic Ensupporting

confidence: 84%

Section: Data Availabilitymentioning

confidence: 99%

See 1 more Smart Citation

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Huelsmann

Hecker

Springer

et al. 2019

Preprint

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“…2013; Peña‐Münzenmayer et al . 2015) have shown that AE4 is Na + dependent. SLC4A11. One of the BTR1 variants has a GXXXP motif.…”

Section: Discussionmentioning

confidence: 99%

Exploring the autoinhibitory domain of the electrogenic Na⁺/HCO₃⁻ transporter NBCe1‐B, from residues 28 to 62

Lee

Boron

2018

The Journal of Physiology

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Variant B of the electrogenic Na /HCO cotransporter (NBCe1-B) contributes to the vectorial transport of HCO in epithelia (e.g. pancreatic ducts) and to the maintenance of intracellular pH in the central nervous systems (e.g. astrocytes). NBCe1-B has very low basal activity due to an autoinhibitory domain (AID) located, at least in part, in the unique portion (residues 1-85) of the cytosolic NH -terminus. Previous work has shown that removing 23 amino acids (residues 40-62) stimulates NBCe1-B. Here, we test the hypothesis that a cationic cluster of nine consecutive positively charged amino acids (residues 40-48) is a necessary part of the AID. Using two-electrode voltage clamping of Xenopus oocytes, we assess the activity of human NBCe1-B constructs in which we systematically replace or delete residues 28-62, which includes the cationic cluster. We find that replacing or deleting all residues within the cationic cluster markedly increases NBCe1-B activity (i.e. eliminates autoinhibition). On the background of a cationic clusterless construct, systematically restoring Arg residues restores autoinhibition in two distinct quanta, with one to three Arg residues restoring ∼50%, and four or more Arg residues restoring virtually all autoinhibition. Systematically deleting residues before the cluster reduces autoinhibition by, at most, a small amount. Replacing or deleting residues after the cluster has no effect. For constructs with low NBCe1 activity (but good surface expression, as assessed by biotinylation), co-expression with super-IRBIT (lacking PP1-binding site) restores full activity (i.e. relieves autoinhibition). In summary, the cationic cluster is a necessary component of the AID of NBCe1-B.

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“…Initial cloning of the gene demonstrated Cl – transport function of the protein, although phylogenetically this isoform is much more closely related to the Na + -coupled HCO 3 – transporters (Alka and Casey, 2014; Ko et al, 2002). Recent evidence suggests that AE4 functions as a Na + -dependent Cl – /HCO 3 – transporter in salivary glands, making AE4 distinct in its transport profile (Pena-Munzenmayer et al, 2015). AE3 is the primary Cl – /HCO 3 – exchanger in the brain, although AE2 is abundant in the choroid plexus (Hentschke et al, 2006; Romero et al, 2013).…”

Section: Acid–base Regulatory Mechanismsmentioning

confidence: 99%

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Zhao

Carney

Falgoust

et al. 2016

Progress in Neurobiology

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Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid–base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na+/H+ exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H+ in exchange for Na+ influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H+ homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies.

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Ae4 (Slc4a9) Anion Exchanger Drives Cl− Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells

Abstract: Background: Salivary glands exhibit a HCO 3 Ϫ -dependent fluid secretion mechanism.

Cited by 33 publications

References 58 publications

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Exploring the autoinhibitory domain of the electrogenic Na⁺/HCO₃⁻ transporter NBCe1‐B, from residues 28 to 62

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

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Ae4 (Slc4a9) Anion Exchanger Drives Cl− Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells

Abstract: Background: Salivary glands exhibit a HCO 3 Ϫ -dependent fluid secretion mechanism.

Cited by 33 publications

References 58 publications

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations

Exploring the autoinhibitory domain of the electrogenic Na+/HCO3− transporter NBCe1‐B, from residues 28 to 62

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

Contact Info

Product

Resources

About

Exploring the autoinhibitory domain of the electrogenic Na⁺/HCO₃⁻ transporter NBCe1‐B, from residues 28 to 62