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.