NAD(P)H oxidase-derived H2O2 signals chloride channel activation in cell volume regulation and cell proliferation

Cellular swelling triggers the activation of Cl- channels (volume-sensitive outwardly rectifying (VSOR) Cl- channels) in many cell types. Ensuing regulatory volume decrease has been considered the primary function of these channels. However, Cl- channels, which share functional properties with volume-sensitive Cl- channels, have been shown to be involved in other physiological processes, including cell proliferation and apoptosis, raising the question of their physiological roles and the signal transduction pathways involved in their activation. Here we report that exogenously applied H2O2 elicited VSOR Cl- channel activation. Furthermore, activation of these channels was found to be coupled to NAD(P) H oxidase activity. Also, epidermal growth factor, known to increase H2O2 production, activated Cl- channels with properties identical to swelling-sensitive Cl- channels. It is concluded that NAD(P) H oxidase-derived H2O2 is the common signal transducing molecule that mediates the activation of these ubiquitously expressed anion channels under a variety of physiological conditions.