A historical overview of chloride transporter research

Abstract Chloride (Cl−) gradients were first studied in muscle cells, erythrocytes, and nephrons during the 1960s and 1970s. Investigation of Cl− gradients expanded into the neuroscience field, as neurobiologists uncovered their important role in inhibitory synaptic transmission. Throughout the 1990s, the genes encoding cation-chloride cotransporters (CCCs), the protein family primarily responsible for establishing Cl− gradients in neurons, were cloned. Contemporaneously, a certain CCC, termed the K+-Cl− cotransporter (KCC2), was shown to play a causal role in hyperpolarizing inhibition in mature neurons. KCC2 is one of nine members of the SLC12A gene family, which display an overall protein identity of ~ 25% and a similar overall structure. CCCs are secondarily active transporters that derive energy from the ionic gradients produced by primary ion transporters to move Cl− across the neuronal plasma membrane. In this chapter we provide a historical overview of the discovery of CCCs, and the subsequent research that characterized their function.