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.