Topological segregation of stress sensors along the gut crypt-villus axis.

The crypt-villus structure of the small intestine serves as an essential protective barrier. The integrity of this barrier is monitored by the complex sensory system of the gut, in which serotonergic enterochromaffin (EC) cells play an important part. These rare sensory epithelial cells surveil the mucosal environment for luminal stimuli and transmit signals both within and outside the gut.

High potency 3-carboxy-2-methylbenzofuran pendrin inhibitors as novel diuretics.

Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC ∼10 μM).

Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration.

Purpose: Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied.

Crypt and Villus Enterochromaffin Cells are Distinct Stress Sensors in the Gut.

The crypt-villus structure of the small intestine serves as an essential protective barrier, with its integrity monitored by the gut's sensory system. Enterochromaffin (EC) cells, which are rare sensory epithelial cells that release serotonin (5-HT), surveil the mucosal environment and signal both within and outside the gut. However, it remains unclear whether EC cells in intestinal crypts and villi respond to different stimuli and elicit distinct responses.

Repurposing calcium-sensing receptor activator drug cinacalcet for ADPKD treatment.

ADPKD is characterized by progressive cyst formation and enlargement leading to kidney failure. Tolvaptan is currently the only FDA-approved treatment for ADPKD; however, it can cause serious adverse effects including hepatotoxicity. There remains an unmet clinical need for effective and safe treatments for ADPKD.

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders.

A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine).

Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells.

Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl- secretion in human intestinal epithelial T84 cells.

Lubiprostone is non-selective activator of cAMP-gated ion channels and Clc-2 has a minor role in its prosecretory effect in intestinal epithelial cells.

Loss of prosecretory Cl channel CFTR activity is considered as the key cause of gastrointestinal disorders in cystic fibrosis including constipation and meconium ileus. Clc-2 is proposed as an alternative Cl channel in intestinal epithelia that can compensate for CFTR loss-of-function. Lubiprostone is an FDA-approved drug with Clc-2 activation as its presumed mechanism of action.

Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis.

Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitute two-thirds of all kidney stones. SLC26A3 (DRA, downregulated in adenoma) is an anion exchanger of chloride, bicarbonate, and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by approximately 70% reduced urine oxalate excretion in knockout mice.