The Strex-Insert in a Stretch-Activated BK Channel from Chick Heart is not Enough for Conferring GsMTx-4 Inhibitory Effect on mSlo1

Abstract

binding to the EGF receptor (EGFR), triggers tyrosine kinase-dependent signaling which effectively down-regulates Kv1.3 currents. However, EGF induces internalization of many membrane proteins, but no evidence linked a decrease of Kv1.3 current amplitude as a consequence of channel endocytosis. Here we describe that Kv1.3 undergoes EGF-dependent endocytosis. Kv1.3 redistribution upon EGFR activation corresponds to induced-endocytosed channels which colocalized intracellular Kv1.3 with endocytic vesicles markers. Our studies revealed that tyrosines and other putative motive sequences are not apparently important for EGFR activation-mediated internalization. However, a putative sequence for ERK1/2-mediated threonine phosphorylation revealed its potential importance in surface Kv1.3 down-regulation. Knock-down of clathrin heavy chain or dynamin II by small interfering RNAs dramatically inhibited EGFR activation-mediated internalization of Kv1.3. We demonstrated that changes in Kv1.3 distribution upon EGFR activation corresponded to a massive Kv1.3 endocytosis via clathrin-coated pits mechanisms which localized the Kv1.3 channels in the lysosomal degradative pathway. This EGF mechanism is highly relevant because halted proliferation but increased neuronal migration from the subventricular zone of the forebrain to the olfactory bulb. Supported by MINECO, Spain (BFU2014-54928-R, BFU2015-70067-REDC and FEDER).