Hypomyelination and increased activity of voltage-gated K+ channels in mice lacking protein tyrosine phosphatase epsilon

Protein tyrosine phosphatase epsilon (PTP epsilon) is strongly expressed in the nervous system; however, little is known about its physiological role. We report that mice lacking PTP epsilon exhibit hypomyelination of sciatic nerve axons at an early post-natal age. This occurs together with increase d activity of delayed-rectifier, voltage-gated potassium (Kv) channels and with hyperphosphorylation of Kv1.5 and Kv2.1 Ky channel alpha-subunits in s ciatic nerve tissue and in primary Schwann cells. PTP epsilon markedly redu ces Kv1.5 or Kv2.1 current amplitudes in Xenopus oocytes. Kv2.1 associates with a substrate-trapping mutant of PTP epsilon, and PTP epsilon profoundly reduces Src- or Fyn-stimulated Kv2.1 currents and tyrosine phosphorylation in transfected HEK 293 cells. In all, PTP epsilon antagonizes activation o f Ky channels by tyrosine kinases ii vive, and affects Schwann cell functio n during a critical period of Schwann cell growth and myelination.