Cation-coupled chloride cotransporters: chemical insights and disease implications
- 1. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia (IIT), Via Morego 30, 16163 Genoa, Italy; Laboratory of Molecular Modeling and Drug Discovery, IIT, Via Morego, 30 16163 Genoa, Italy
- 2. Laboratory of Molecular Modeling and Drug Discovery, IIT, Via Morego, 30 16163 Genoa, Italy
- 3. Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia (IIT), Via Morego 30, 16163 Genoa, Italy; Dulbecco Telethon Institute, Via Varese 16b, 00185 Rome, Italy
Description
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.
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Related works
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- Journal article: 10.1016/j.trechm.2021.05.004 (DOI)
Funding
- 3D NKCC1 – Interdisciplinary approach to characterize the structure and the ion transport mechanism of NKCC1, a key target for brain disorders. 843239
- European Commission
- GenEdiDS – Rescuing Cognitive Deficits in Neurodevelopmental Disorders by Gene Editing in Brain Development: the Case of Down Syndrome 725563
- European Commission