A Novel Function of Ionotropic γ-Aminobutyric Acid Receptors Involving Alveolar Fluid Homeostasis

Abstract

Polarized distribution of chloride channels on the plasma membrane of epithelial cells is required for fluid transport across the epithelium of fluid-transporting organs. Ionotropic gamma-aminobutyric acid receptors are primary ligand-gated chloride channels that mediate inhibitory neurotransmission. Traditionally, these receptors are not considered to be contributors to fluid transport. Here, we report a novel function of gamma-aminobutyric acid receptors involving alveolar fluid homeostasis in adult lungs. We demonstrated the expression of functional ionotropic gamma-aminobutyric acid receptors on the apical plasma membrane of alveolar epithelial type II cells. gamma-Aminobutyric acid significantly increased chloride efflux in the isolated type II cells and inhibited apical to basolateral chloride transport on type II cell monolayers. Reduction of the gamma-aminobutyric acid receptor pi subunit using RNA interference abolished the gamma-aminobutyric acid-mediated chloride transport. In intact rat lungs, gamma-aminobutyric acid inhibited both basal and beta agonist-stimulated alveolar fluid clearance. Thus, we provide molecular and pharmacological evidence that ionotropic gamma-aminobutyric acid receptors contribute to fluid transport in the lung via luminal secretion of chloride. This finding may have the potential to develop clinical approaches for pulmonary diseases involving abnormal fluid dynamics.