Fig. 2. Overview of ion transporters and channels, which are responsible for setting intracellular Cl⁻ levels in neural cells.

The transmembrane gradients of Na⁺ and K⁺ are established by the Na⁺/K⁺-ATPases (NKA). The negative charge on the plasmalemmal membrane passively drives Cl⁻ outside of the cell via a plethora of mechanisms, which are collectively termed Cl⁻ “leak”. However, in neurons and astrocytes [Cl⁻]_i deviates from the levels predicted by the electrochemical equilibrium due to the activity of the Na⁺,K⁺,2Cl⁻ cotransporter (NKCC1) and/or the K⁺,Cl⁻ cotransporters (KCC1-4). Opening of voltage-gated Cl⁻ channels (VGCC), ligand-gated Cl⁻ channels (LGCC), or volume-regulated anion channels (VRAC) moves Cl⁻ in or out of the cell, depending on the electrochemical driving force. Additionally, Cl⁻ movement also occurs via the Cl⁻/HCO₃⁻ anion exchangers (AE3 and others).