K+-Cl− co-transporter 2 (KCC2)–a membrane trafficking perspective

Abstract

K+-Cl− co-transporter 2 (KCC2/SLC12A5) is a neuronal specific cation chloride co-transporter which is active under isotonic conditions, and thus a key regulator of intracellular Cl− levels. It also has an ion transporter-independent structural role in modulating the maturation and regulation of excitatory glutamatergic synapses. KCC2 levels are developmentally regulated, and a postnatal upregulation of KCC2 generates a low intracellular chloride concentration that allows the neurotransmitters γ-aminobutyric acid (GABA) and glycine to exert inhibitory neurotransmission through its Cl− permeating channel. Functional expression of KCC2 at the neuronal cell surface is necessary for its activity, and impairment in KCC2 cell surface transport and/or internalization may underlie a range of neuropathological conditions. Although recent advances have shed light on a range of cellular mechanisms regulating KCC2 activity, little is known about its membrane trafficking itinerary and regulatory proteins. In this review, known membrane trafficking signals, pathways and mechanisms pertaining to KCC2’s functional surface expression are discussed.