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Vol. 17, Issue 10, 4330-4342, October 2006

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Tyrosine Phosphatases and Perform Specific and Overlapping Functions in Regulation of Voltage-gated Potassium Channels in Schwann Cells

Zohar Tiran^*, Asher Peretz, Tal Sines^*, Vera Shinder, Jan Sap^,||, Bernard Attali, and Ari Elson^*

Departments of *Molecular Genetics and Chemical Research Support, The Weizmann Institute of Science, Rehovot 76100, Israel; Department of Physiology and Pharmacology, Tel Aviv University Medical School, Tel Aviv 69978, Israel; and Department of Pharmacology, New York University Medical School, New York, NY 10016

Submitted February 24, 2006; Revised June 20, 2006; Accepted July 17, 2006
Monitoring Editor: Carl-Henrik Heldin

Tyrosine phosphatases (PTPs) and are closely related and share several molecular functions, such as regulation of Src family kinases and voltage-gated potassium (Kv) channels. Functional interrelationships between PTP and PTP and the mechanisms by which they regulate K⁺ channels and Src were analyzed in vivo in mice lacking either or both PTPs. Lack of either PTP increases Kv channel activity and phosphorylation in Schwann cells, indicating these PTPs inhibit Kv current amplitude in vivo. Open probability and unitary conductance of Kv channels are unchanged, suggesting an effect on channel number or organization. PTP inhibits Kv channels more strongly than PTP; this correlates with constitutive association of PTP with Kv2.1, driven by membranal localization of PTP. PTP, but not PTP, activates Src in sciatic nerve extracts, suggesting Src deregulation is not responsible exclusively for the observed phenotypes and highlighting an unexpected difference between both PTPs. Developmentally, sciatic nerve myelination is reduced transiently in mice lacking either PTP and more so in mice lacking both PTPs, suggesting both PTPs support myelination but are not fully redundant. We conclude that PTP and PTP differ significantly in their regulation of Kv channels and Src in the system examined and that similarity between PTPs does not necessarily result in full functional redundancy in vivo.

^||Present address: Department of Molecular Pathology, The University of Copenhagen, Frederik V vej 11, 6. sal, 2100-København Ø, Denmark.

Address correspondence to: Ari Elson (ari.elson{at}weizmann.ac.il)

Abbreviations used: Kv channel, delayed rectifier, voltage-gated K⁺ channel, ; PTP, protein tyrosine phosphatase.

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