Hypoxia-Induced Neurite Outgrowth Involves Regulation Through TRPM7.

Abstract

Transient receptor potential melastatin 7 (TRPM7) is a ubiquitously expressed divalent cation channel that plays a key role in cell functions such as ion homeostasis, cell proliferation, survival, and cytoskeletal dynamics and mediates cells death in hypoxic and ischemic conditions. Previously, TRPM7 was found to play a role in the neurite outgrowth and maturation of primary hippocampal neurons. Either knockdown of TRPM7 with target-specific shRNA or blocking channel conductance by a specific blocker waixenicin A enhanced axonal outgrowth in the primary neuronal culture. In this study, we investigated whether and how TPRM7 is involved in hypoxia-altered neurite outgrowth patterns in E16 hippocampal neuron cultures. We demonstrate that short-term hypoxia activated the MEK/ERK and PI3K/Akt pathways, reduced TRPM7 activity, and enhanced axonal outgrowth of neuronal cultures. On the other hand, long-term hypoxia caused a progressive retraction of axons and dendrites that could be attenuated by the TRPM7-specific inhibitor waixenicin A. Further, we demonstrate that in the presence of astrocytes, axonal retraction in long-term hypoxic conditions was enhanced, and TRPM7 block by waixenicin A prevented this retraction. Our data demonstrate the effect of hypoxia on TRPM7 activity and axonal outgrowth/retraction in cultures with or without astrocytes present.