Cells are constantly exposed to changes in cell volume during cell metabolism, nutrient uptake, cell proliferation, cell migration and salt and water transport. In order to cope with these perturbations, potassium channels in line with chloride channels have been shown to be likely contributors to the process of cell volume adjustments. A great diversity of potassium channels being members of either the 6TM, 4 TM or 2 TM K+ channel gene family have been shown to be strictly regulated by small, fast changes in cell volume. However, the precise mechanism underlying the K+ channel sensitivity to cell volume alterations is not yet fully understood. The KCNQ1 channel belonging to the voltage gated KCNQ family is considered a precise sensor of volume changes. The goal of this thesis was to elucidate the mechanism that induces cell volume sensitivity. Until now, a number of investigators have implicitly assumed that changes in cell volume are associated with parallel changes in membrane stretch, and, consequently, that regulation by cell volume and by membrane stretch constitute a common regulatory mechanism. This assumption was challenged in Manuscript I where we analyzed and compared the effects of (1) osmotic cell swelling and (2) local membrane stretch on the highly volume sensitive KCNQ1 channel and the highly stretch sensitive BK channel. In this study we present evidence against this assumption by showing that activation of BK channels by local membrane stretch is not mimicked by cell swelling, and activation of KCNQ1 channels by cell volume increase is not mimicked by stretch of the cell membrane. Thus, we conclude that stretch- and volume-sensitivity can be considered two independent regulatory mechanisms. Alternatively, volume-activation of ion channels could be mediated by an autocrine mechanism in which ATP released from the cells in response to volume changes activates signaling pathways that subsequently lead to ion channel stimulation. Whether volume sensitivity of KCNQ1 is modulated by ATP release was investigated in Manuscript II. ATP release from KCNQ1 injected oocytes was monitored by a Luciferin/Luciferase assay during cell volume changes and the effect of exogenously added ATP and apyrase on the cell volume induced KCNQ1 current was studied. Based on our data to date, we postulate that KCNQ1 does not seem to be responsive to ATP during cell volume changes, which indicates another mechanism of regulation. Besides being regulated by cell volume, KCNQ1 is also modulated by the interaction of the ß subunit KCNE1 giving rise to the cardiac IKs delayed rectifier potassium current. Apart from altering the kinetic characteristics of the KCNQ1 channel current, KCNE1 also augments the KCNQ1 current. It is debated whether this increase in macroscopic current upon expression of KCNQ1 with KCNE1 is due to an increase in ion channel conductance (¿), the open state probability (Po) or an increase in the number of channels in the plasma membrane (N). The latter was quantified by measuring the level of KCNQ1 surface expression by using an enzyme-linked immunoassay (Manuscript III). To do this, a HA-tagged version of the KCNQ1 channel was expressed with and without KCNE1 in Xenopus oocytes. The results show that the KCNQ1 surface expression was significantly lower when KCNE1 is coexpressed compared to KCNQ1 alone despite the higher current for the heteromeric KCNQ1/KCNE1. This indicates that the overall increase of the KCNQ1 current, when KCNE1 is coexpressed, is not due to an increase in ion channel surface density but rather to an increase in single-channel conductance or in open state probability.