Cl⁻ as a bona fide signaling ion

Cl − is the major extracellular (Cl − out ) and intracellular (Cl − in ) anion whose concentration is actively regulated by multiple transporters. These transporters generate Cl − gradients across the plasma membrane and between the cytoplasm and intracellular organelles. [Cl − ] in changes rapidly in response to cell stimulation and influences many physiological functions, as well as cellular and systemic homeostasis. However, less appreciated is the signaling function of Cl − . Cl − interacts with multiple proteins to directly modify their activity. This review highlights the signaling function of Cl − and argues that Cl − is a bona fide signaling ion, a function deserving extensive exploration.