icl swell is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of icl swell. In platelets, ICln binds to the intracellular domain of the integrin αIIb chain, however, whether the ICln/integrin interaction plays a role in RVD is not known. Here we show that a direct molecular interaction between ICln and the integrin α-chain is not restricted to platelets and involves highly conserved amino acid motifs. integrin α recruits ICln to the plasma membrane, thereby facilitating the activation of ICl swell during hypotonicity. Perturbation of the ICln/integrin interaction prevents the transposition of ICln towards the cell surface and, in parallel, impedes the activation of ICl swell. We suggest that the ICln/integrin interaction interface may represent a new molecular target enabling specific ICl swell suppression in pathological conditions when this current is deregulated or plays a detrimental role. Cellular volume changes occur in a variety of physiological processes, including transepithelial transport, cell migration, proliferation, and death. As limiting excessive or prolonged volume changes is essential for normal cell function and survival, most cell types are able to counteract volume perturbations by initiating the homeostatic processes of regulatory volume increase and decrease (RVI and RVD, respectively) 1-4. Activation of a chloride conductance upon cell swelling (ICl swell) is a key step in RVD and occurs via volume regulated anion channels (VRACs) 5,6. The mechanisms of osmosensing are complex and far from being completely understood. Several lines of evidence implicate integrins as upstream sensors of cell volume perturbations in mammalian cells after cell swelling or shrinkage 1,7-9. Integrins are a highly conserved family of heterodimeric adhesion molecules that consist of an αand a β-subunit and connect the extracellular matrix to intracellular signalling proteins and the cytoskeleton, and play a critical role in many vital cellular functions, such as cell adhesion, migration, invasion, differentiation, proliferation, apoptosis, growth-factor signalling and response to hypotonicity 10-13. By linking the exterior and interior space of cells, integrins permit a bidirectional transmission (outside-in and inside-out signalling) of mechanical and biochemical stimuli across the plasma membrane 14,15. Specifically, activation of integrins by hypotonicity 16 seems to trigger Cl − and organic osmolyte fluxes during RVD, possibly by recruitment of a member of the SRC family of kinases 17. Integrins also establish an intricate network of molecular interactions via their intracellular domains. The β-subunits are major players in this context, and bind signalling hubs such as talin and kindlins 18-20. The intracellular network of the α-subunits was less extensively studied. Evidence was gathered that the ...