Cation-coupled chloride cotransporters: chemical insights and disease implications

Corinne Portioli; Manuel José Ruiz Munevar; Marco De Vivo; Laura Cancedda

doi:10.1016/j.trechm.2021.05.004

Cation-coupled chloride cotransporters: chemical insights and disease implications

Trends Chem. 2021 Oct;3(10):832-849. doi: 10.1016/j.trechm.2021.05.004.

Authors

Corinne Portioli^{1

2}, Manuel José Ruiz Munevar², Marco De Vivo², Laura Cancedda^{1

3}

Affiliations

¹ Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia (IIT), Via Morego 30, 16163 Genoa, Italy.
² Laboratory of Molecular Modeling and Drug Discovery, IIT, Via Morego, 30 16163 Genoa, Italy.
³ Dulbecco Telethon Institute, Via Varese 16b, 00185 Rome, Italy.

Abstract

Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies.

Keywords: CCC physiology; cryo-EM; ion-binding sites; membrane transporters; selective drugs; structural biology.

Publication types

Review