Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Through regulation of excretion, the kidney shares responsibility for the metabolic balance of calcium (Ca(2+)) with several other tissues including the GI tract and bone. The balances of Ca(2+) and phosphate (PO4), magnesium (Mg(2+)), sodium (Na(+)), potassium (K(+)), chloride (Cl(-)), and water (H2O) are linked via regulatory systems with overlapping effects and are also controlled by systems specific to each of them. Cloning of the calcium-sensing receptor (CaSR) along with the recognition that mutations in the CaSR gene are responsible for two familial syndromes characterized by abnormalities in the regulation of PTH secretion and Ca(2+) metabolism (Familial Hypocalciuric Hypercalcemia, FHH, and Autosomal Dominant Hypocalcemia, ADH) made it clear that extracellular Ca(2+) (Ca(2+)o) participates in its own regulation via a specific, receptor-mediated mechanism. Demonstration that the CaSR is expressed in the kidney as well as the parathyroid glands combined with more complete characterizations of FHH and ADH established that the effects of elevated Ca(2+) on the kidney (wasting of Na(+), K(+), Cl(-), Ca(2+), Mg(2+) and H2O) are attributable to activation of the CaSR. The advent of positive and negative allosteric modulators of the CaSR along with mouse models with global or tissue-selective deletion of the CaSR in the kidney have allowed a better understanding of the functions of the CaSR in various nephron segments. The biology of the CaSR is more complicated than originally thought and difficult to define precisely owing to the limitations of reagents such as anti-CaSR antibodies and the difficulties inherent in separating direct effects of Ca(2+) on the kidney mediated by the CaSR from associated CaSR-induced changes in PTH. Nevertheless, renal CaSRs have nephron-specific effects that contribute to regulating Ca(2+) in the circulation and urine in a manner that assures a narrow range of Ca(2+)o in the blood and avoids excessively high concentrations of Ca(2+) in the urine.
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PMID:Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. 2385 64

Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder.
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PMID:The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). 2605 99