Background/Aims: Osmotic swelling of Muller cells is a common phenomenon in animal models of ischemic and diabetic retinopathies. Muller cells possess a swelling-inhibitory purinergic signaling cascade which can be activated by various receptor ligands including vascular endothelial growth factor (VEGF) and glutamate. Here, we investigated whether deletion of P2Y(1) (P2Y(1)R) and adenosine A(1) receptors (A(1)AR), and of inositol-1,4,5-trisphosphate-receptor type 2 (IP(3)R2), in mice affects the inhibitory action of VEGF and glutamate on Muller cell swelling. Methods: The cross-sectional area of Muller cell somata was recorded after a 4-min superfusion of retinal slices with a hypoosmotic solution. Results: Hypoosmolarity induced a swelling of Muller cells from P2Y(1)R(-/-), A(1)AR(-/-) and IP(3)R2(-/-) mice, but not from wild-type mice. Swelling of wild-type Muller cells was induced by hypoosmotic solution containing barium chloride. Whereas VEGF inhibited the swelling of wild-type Muller cells, it had no swelling-inhibitory effect in cells from A(1)AR(-/-) and IP(3)R2(-/-) mice. Glutamate inhibited the swelling of wild-type Muller cells but not of cells from P2Y(1)R(-/-), A(1)AR(-/-) and IP(3)R2(-/-) animals. Conclusion: The swelling-inhibitory effects of VEGF and glutamate in murine Muller cells is mediated by transactivation of P2Y(1)R and A(1)AR, as well as by intracellular calcium signaling via activation of IP(3)R2. Copyright (C) 2013 S. Karger AG, Basel