Tyrosine phosphatases epsilon and alpha perform specific and overlapping functions in regulation of voltage-gated potassium channels in Schwann cells.
Tyrosine phosphatases (PTPs) epsilon and alpha are closely related and share several molecular functions, such as regulation of Src family kinases and voltage-gated potassium (Kv) channels. Functional interrelationships between PTPepsilon and PTPalpha 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. PTPalpha inhibits Kv channels more strongly than PTPepsilon; this correlates with constitutive association of PTPalpha with Kv2.1, driven by membranal localization of PTPalpha. PTPalpha, but not PTPepsilon, 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 PTPepsilon and PTPalpha 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.
Tiran
Zohar
Z
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Peretz
Asher
A
Sines
Tal
T
Shinder
Vera
V
Sap
Jan
J
Attali
Bernard
B
Elson
Ari
A
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism* / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve / Q000378:metabolism; D051669:Shab Potassium Channels / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases