Molecular Operation of the Cation Chloride Cotransporters: Ion Binding and Inhibitor Interaction

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Abstract

The cation chloride cotransporters (CCCs) represent an important family of transporters that plays key roles in vectorial electrolyte movement across epithelia and in intracellular chloride homeostasis of neurons and muscle cells. The CCCs are composed of three broad groups, two of which include multiple isoforms: Na-Cl cotransporter (NCC; SLC12A3), Na-K-2Cl cotransporter (NKCC; SLC12A1-2), and K-Cl cotransporter (KCC; SLC12A4-7). The CCCs are inhibited by clinically relevant drugs, including loop diuretics that inhibit NKCC2 in the renal thick ascending limb and thiazide diuretics that inhibit NCC in the renal distal tubule. For many years, much research on this gene family has centered on understanding ion binding and inhibitor interaction which represent important features of the molecular operation of these transporters. Recently, high resolution structures of bacterial transport proteins related to the CCCs have become available, thus permitting structural context in which to evaluate previous ion and inhibitor studies of the CCCs. In this article, I review past molecular and structure-function studies that have provided key pieces of information about ion binding and inhibitor interaction primarily of NKCC for which we have the most information. I then place these findings into the structural context of recent homology models of NKCC based on the outward-facing open and occluded conformations of the related bacterial transporters. These homology models provide our first glimpse into the fine details of the molecular operation of the CCCs.

Original languageEnglish (US)
Pages (from-to)215-237
Number of pages23
JournalCurrent Topics in Membranes
Volume70
DOIs
StatePublished - 2012

Fingerprint

Cations
Chlorides
Ions
Member 1 Solute Carrier Family 12
Member 3 Solute Carrier Family 12
Distal Kidney Tubule
Sodium Potassium Chloride Symporter Inhibitors
Sodium Chloride Symporter Inhibitors
Bacterial Proteins
Molecular Structure
Muscle Cells
Electrolytes
Carrier Proteins
Protein Isoforms
Homeostasis
Extremities
Epithelium
Kidney
Neurons
Research

Keywords

  • Chloride homeostasis
  • Chloride transport
  • Diuretics
  • Translocation pocket
  • Transporter structure

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

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abstract = "The cation chloride cotransporters (CCCs) represent an important family of transporters that plays key roles in vectorial electrolyte movement across epithelia and in intracellular chloride homeostasis of neurons and muscle cells. The CCCs are composed of three broad groups, two of which include multiple isoforms: Na-Cl cotransporter (NCC; SLC12A3), Na-K-2Cl cotransporter (NKCC; SLC12A1-2), and K-Cl cotransporter (KCC; SLC12A4-7). The CCCs are inhibited by clinically relevant drugs, including loop diuretics that inhibit NKCC2 in the renal thick ascending limb and thiazide diuretics that inhibit NCC in the renal distal tubule. For many years, much research on this gene family has centered on understanding ion binding and inhibitor interaction which represent important features of the molecular operation of these transporters. Recently, high resolution structures of bacterial transport proteins related to the CCCs have become available, thus permitting structural context in which to evaluate previous ion and inhibitor studies of the CCCs. In this article, I review past molecular and structure-function studies that have provided key pieces of information about ion binding and inhibitor interaction primarily of NKCC for which we have the most information. I then place these findings into the structural context of recent homology models of NKCC based on the outward-facing open and occluded conformations of the related bacterial transporters. These homology models provide our first glimpse into the fine details of the molecular operation of the CCCs.",
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N2 - The cation chloride cotransporters (CCCs) represent an important family of transporters that plays key roles in vectorial electrolyte movement across epithelia and in intracellular chloride homeostasis of neurons and muscle cells. The CCCs are composed of three broad groups, two of which include multiple isoforms: Na-Cl cotransporter (NCC; SLC12A3), Na-K-2Cl cotransporter (NKCC; SLC12A1-2), and K-Cl cotransporter (KCC; SLC12A4-7). The CCCs are inhibited by clinically relevant drugs, including loop diuretics that inhibit NKCC2 in the renal thick ascending limb and thiazide diuretics that inhibit NCC in the renal distal tubule. For many years, much research on this gene family has centered on understanding ion binding and inhibitor interaction which represent important features of the molecular operation of these transporters. Recently, high resolution structures of bacterial transport proteins related to the CCCs have become available, thus permitting structural context in which to evaluate previous ion and inhibitor studies of the CCCs. In this article, I review past molecular and structure-function studies that have provided key pieces of information about ion binding and inhibitor interaction primarily of NKCC for which we have the most information. I then place these findings into the structural context of recent homology models of NKCC based on the outward-facing open and occluded conformations of the related bacterial transporters. These homology models provide our first glimpse into the fine details of the molecular operation of the CCCs.

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