Cellular uptake of amino acids: Systems and regulation

Amino acids perform a variety of functions in mammalian cells. They not only serve as the building blocks for protein synthesis but also play additional important roles in neurotransmission, production and storage of metabolic energy, nitrogen metabolism, and synthesis of hormones, purine and pyrimidine nucleotides, and glutathione. The intracellular pool of amino acids is derived not only from endogenous production (biosynthesis as well as protein degradation) but also from transfer across the plasma membrane. Due to their ionic nature, amino acids do not permeate biological membranes by diffusion to any great extent. Transfer across biological membranes therefore requires participation of specific transport proteins. This transfer process does not necessarily have to serve only the entry of amino acids into cells. This process also mediates the exit of certain amino acids in a tissue-specific manner. In a number of cases, the transfer involves exchange across the membrane, a process that couples the entry of certain amino acids into cells and the exit of different amino acids from the cells. A multitude of transport systems is known to facilitate the transfer of amino acids across the plasma membrane in mammalian cells. These transport systems exhibit variable but in many instances overlapping substrate specificity and are not expressed uniformly in all cell types. The differential expression of amino acid transport systems coupled with their variable substrate specificity has physiological significance because different tissue types vary markedly in their requirements for specific amino acids to suit their specific physiological functions. In addition to the differences in substrate specificity, the amino acid transport systems also differ in their energetics and hence in their transport mechanism. Some transport systems are passive, functioning either as uniporters or exchangers without involving any driving force, whereas others are active, driven by transmembrane ion gradients. In many cases, multiple ion gradients are involved in the energization process, thus enhancing the concentrative capacity of the transport systems.