Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice.

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain.

NH/NH allosterically activates SLC4A11 by causing an acidic shift in the intracellular pK that governs H(OH) conductance.

SLC4A11 is the most abundant membrane transport protein in corneal endothelial cells. Its functional presence is necessary to support the endothelial fluid pump that draws fluid from the corneal stroma, preventing corneal edema. Several molecular actions have been proposed for SLC4A11 including HO transport and cell adhesion.

NBCe1-B/C-knockout mice exhibit an impaired respiratory response and an enhanced renal response to metabolic acidosis.

The sodium-bicarbonate cotransporter (NBCe1) has three primary variants: NBCe1-A, -B and -C. NBCe1-A is expressed in renal proximal tubules in the cortical labyrinth, where it is essential for reclaiming filtered bicarbonate, such that NBCe1-A knockout mice are congenitally acidemic. NBCe1-B and -C variants are expressed in chemosensitive regions of the brainstem, while NBCe1-B is also expressed in renal proximal tubules located in the outer medulla.

Corneal dystrophy mutations R125H and R804H disable SLC4A11 by altering the extracellular pH dependence of the intracellular pK that governs H(OH) transport.

Mutations in the H(OH) conductor SLC4A11 result in corneal endothelial dystrophy. In previous studies using mouse Slc4a11, we showed that the pK value that governs the intracellular pH dependence of SLC4A11 (pK) is influenced by extracellular pH (pH). We also showed that some mutations result in acidic or alkaline shifts in pK, indicating that the pH dependence of SLC4A11 is important for physiological function.

Revisiting the Role of Ser982 Phosphorylation in Stoichiometry Shift of the Electrogenic Na/HCO Cotransporter NBCe1.

In most cell types and heterologous expression systems, the electrogenic sodium-bicarbonate cotransporter NBCe1 operates with a 1Na-2HCO stoichiometry that, given typical transmembrane electrochemical gradients, promotes Na+ and HCO influx. However, NBCe1 in the kidney mediates HCO efflux (HCO reabsorption), a direction that has been predicted to be favored only if NBCe1 operates with a 1:3 stoichiometry. The phosphorylation state of Ser982 in the cytosolic carboxy-terminal domain of NBCe1 has been reported to be a key determinant of the transporter stoichiometry, with non-phosphorylated Ser982 favoring a 1:3 stoichiometry.

pH dependence of the Slc4a11-mediated H conductance is influenced by intracellular lysine residues and modified by disease-linked mutations.

SLC4A11 is the only member of the SLC4 family that transports protons rather than bicarbonate. SLC4A11 is expressed in corneal endothelial cells, and its mutation causes corneal endothelial dystrophy, although the mechanism of pathogenesis is unknown. We previously demonstrated that the magnitude of the H conductance () mediated by SLC4A11 is increased by rises in intracellular as well as extracellular pH (pH and pH).

Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice.

Background: The gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning.

The role of disease-linked residue glutamine-913 in support of the structure and function of the human electrogenic sodium/bicarbonate cotransporter NBCe1-A.

Mutations in the sodium bicarbonate cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA). We recently described a novel pRTA mutation p.Gln913Arg (Q913R), inherited in compound heterozygous form with p.

A novel mutant Na /HCO3 cotransporter NBCe1 in a case of compound-heterozygous inheritance of proximal renal tubular acidosis.

Key Points: The inheritance of two defective alleles of SLC4A4, the gene that encodes the widely-expressed electrogenic sodium bicarbonate cotransporter NBCe1, results in the bicarbonate-wasting disease proximal renal tubular acidosis (pRTA). In the present study, we report the first case of compound-heterozygous inheritance of pRTA (p.Arg510His/p.

Mouse Slc4a11 expressed in Xenopus oocytes is an ideally selective H+/OH- conductance pathway that is stimulated by rises in intracellular and extracellular pH.

The SLC4A11 gene encodes the bicarbonate-transporter-related protein BTR1, which is mutated in syndromes characterized by vision and hearing loss. Signs of these diseases [congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome] are evident in mouse models of Slc4a11 disruption. However, the intrinsic activity of Slc4a11 remains controversial, complicating assignment of its (patho)physiological role.

Divergent effects of ERα and ERβ on fluid intake by female rats are not dependent on concomitant changes in AT1R expression or body weight.

Estradiol (E2) decreases both water and saline intakes by female rats. The ERα and ERβ subtypes are expressed in areas of the brain that control fluid intake; however, the role that these receptors play in E2's antidipsogenic and antinatriorexigenic effects have not been examined. Accordingly, we tested the hypothesis that activation of ERα and ERβ decreases water and saline intakes by female rats.

Roux-en-Y gastric bypass does not affect daily water intake or the drinking response to dipsogenic stimuli in rats.

Bariatric surgery is currently the most effective treatment for severe obesity, and Roux-en-Y gastric bypass (RYGB) is the most common approach in the United States and worldwide. Many studies have documented the changes in body weight, food intake, and glycemic control associated with the procedure. Although dehydration is commonly listed as a postoperative complication, little focus has been directed to testing the response to dipsogenic treatments after RYGB.

Sex differences in corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity.

Background: Women are twice as likely as men to suffer from stress-related affective disorders. Corticotropin-releasing factor (CRF) is an important link between stress and mood, in part through its signaling in the serotonergic dorsal raphe (DR). Development of CRF receptor-1 (CRFr1) antagonists has been a focus of numerous clinical trials but has not yet been proven efficacious.

Activation of membrane-associated estrogen receptors decreases food and water intake in ovariectomized rats.

Estradiol (E2) decreases food and water intake in a variety of species, including rats. Available evidence suggests that this is mediated by genomic mechanisms that are most often attributed to nuclear estrogen receptors. More recent studies indicate that membrane-associated estrogen receptors (mERs) also can influence gene expression through the activation of transcription factors, yet it is unclear whether mERs are involved in mediating the hypophagic and antidipsetic effects of E2.

Evaluating the potential for rostral diffusion in the cerebral ventricles using angiotensin II-induced drinking in rats.

In spite of evidence to the contrary, concern that substances injected into the fourth ventricle (4V) reach forebrain structures challenges the validity of using these injections to evaluate the role of hindbrain structures. Injection of AngII into the lateral ventricle (LV) increases water intake, but a similar response is not observed after injection into the 4V. This alone suggests the requirement of forebrain structures, but the potential for a counteracting, anti-dipsogenic pressor response to hindbrain AngII allows for lingering concern that this competing effect of AngII, rather than lack of forebrain access, underlies the negative result.