The K+ channels Kir4.1 and Kir4.1-Kir5.1 are expressed in the glial cells of the CNS and are involved in regulation of the K+ homeostasis. Several studies have shown that Kir4.1 channels are co-localized with aquaporins (AQP4) in the glial endfeet, and a putative functional coupling between the Kir channels and aquaporins is therefore debated. To test a possible volume-sensitivity of the Kir channels, the Kir4.1 or Kir4.1-Kir5.1 channels were expressed in Xenopus oocytes with or without co-expression of aquaporins and subsequently exposed to cell volume alterations. Our results show an increase in Kir4.1 and Kir4.1-Kir5.1 currents upon swelling of the oocytes and a reduction in the current when the oocytes were shrunk. The volume-dependent changes in channel activity were not due to changes in the kinetics of the channels. These findings implicate a putative functional interaction between the Kir channels and aquaporins via small, fast cell volume changes in the glial cells.