The High-Affinity Glutamate and Neutral Amino-Acid Transporter Family: Structure, Function, and Physiological Relevance

Abstract

The classical studies in transport physiology revealed that neurons, glial cells, and epithelial cells possess unique Na+and K+-dependent glutamate transporters with either a high affinity (Km =1–50 μM) or a low affinity (Km >100 μM) for glutamate (1–8). The high-affinity transporters have been identified through various approaches. They belong to a single gene superfamily, called SLC1, which also includes genes encoding the neutral amino-acid transporters (Table 1). The genes encoding low-affinity glutamate transporters (7,8) have not yet been identified. The high-affinity transporters are distinct from the recently identified vesicular glutamate transporters which belong to the SLC17 family of transporters, originally believed to be type I Na+/phosphate transporters (9–11). Briefly, the vesicular glutamate transporters mediate glutamate uptake into synaptic vesicles, driven by the vesicular-membrane potential, which is maintained by the vacuolar H+-ATPase. There are two vesicular glutamate transporter isoforms, called VGluT1 and VGluT2 (see Chapter 9). Both of these transporters are exclusively expressed in glutamatergic synapses, with complementary tissue distribution within the central nervous system (CNS). The main purpose of this chapter is to review recent insights into the structure, in vivo functional roles, and pathological implications of the mammalian highaffinity glutamate transporters (SLC1 family). The chapter also explores recent progress in characterizing related neutral amino-acid transporters.