Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of hippocampal neurons

The development of hyperpolarizing inhibition is an important step in the m aturation of neuronal networks. Hyperpolarizing inhibition requires Cl- out ward transport that is accomplished by KCC2, a K+/Cl- cotransporter. We sho w that cultured hippocampal neurons initially contain an inactive form of t he KCC2 protein, which becomes activated during subsequent maturation of th e neurons. We also show that this process is accelerated by transient stimu lation of IGF-1 receptors. Because the transporter can be rapidly activated by coapplication of IGF-1 and an Src kinase and can be deactivated by memb rane-permeable protein tyrosine kinase inhibitors, we suggest that activati on of K+/Cl- cotransporter function by endogenous protein tyrosine kinases mediates the developmental switch of GABAergic responses to hyperpolarizing inhibition.