Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology

Abstract

Transporters of the solute carrier family 12 (SLC12) carry inorganic cations such as Na⁺ and/or K⁺ alongside Cl across the plasma membrane of cells. These tightly coupled, electroneutral, transporters are expressed in almost all tissues/organs in the body where they fulfil many critical functions. The family includes two key transporters participating in salt reabsorption in the kidney: the Na-K-2Cl cotransporter-2 (NKCC2), expressed in the loop of Henle, and the Na-Cl cotransporter (NCC), expressed in the distal convoluted tubule. NCC and NKCC2 are the targets of thiazides and "loop" diuretics, respectively, drugs that are widely used in clinical medicine to treat hypertension and edema. Bumetanide, in addition to its effect as a loop diuretic, has recently received increasing attention as a possible therapeutic agent for neurodevelopmental disorders. This chapter also describes how over the past two decades, the pharmacology of Na⁺ independent transporters has expanded significantly to provide novel tools for research. This work has indeed led to the identification of compounds that are 100-fold to 1000-fold more potent than furosemide, the first described inhibitor of K-Cl cotransport, and identified compounds that possibly directly stimulate the function of the K-Cl cotransporter. Finally, the recent cryo-electron microscopy revolution has begun providing answers as to where and how pharmacological agents bind to and affect the function of the transporters.

Keywords: Bumetanide; Cation–chloride cotransporters; Chloride dye; Cryo-EM structure; High-throughput screening; Ion binding; Kidney; N-ethylmaleimide; Neurodevelopmental disorders; Protein–ligand complex; Thallium dyes; Thiazide and loop diuretics.