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

Abstract

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