J. Cell Biol., Volume 141, Number 1, April 6, 1998 281-286

The Tyrosine Kinase p56^lck Mediates Activation of Swelling-induced Chloride Channels in Lymphocytes

Albrecht Lepple-Wienhues, Ildikò Szabò, Tilmann Laun, Nubia Kristen Kaba, Erich Gulbins, and Florian Lang

Department of Physiology, University of Tübingen, D-72076 Tübingen, Germany

Osmotic cell swelling activates Cl channels to achieve anion efflux. In this study, we find that both the tyrosine kinase inhibitor herbimycin A and genetic knockout of p56^lck, a src-like tyrosine kinase, block regulatory volume decrease (RVD) in a human T cell line. Activation of a swelling-activated chloride current (I_Clswell) by osmotic swelling in whole-cell patch-clamp experiments is blocked by herbimycin A and lavendustin. Osmotic activation of I_Clswell is defective in p56^lck-deficient cells. Retransfection of p56^lck restores osmotic current activation. Furthermore, tyrosine kinase activity is sufficient for activation of I_Clswell. Addition of purified p56^lck to excised patches activates an outwardly rectifying chloride channel with 31 pS unitary conductance. Purified p56^lck washed into the cytoplasm activates I_Clswell in native and p56^lck-deficient cells even when hypotonic intracellular solutions lead to cell shrinkage. When whole-cell currents are activated either by swelling or by p56^lck, slow single-channel gating events can be observed revealing a unitary conductance of 25-28 pS. In accordance with our patch-clamp data, osmotic swelling increases activity of immunoprecipitated p56^lck. We conclude that osmotic swelling activates I_Clswell in lymphocytes via the tyrosine kinase p56^lck.

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