Sodium-coupled Secondary Transporters: Insights from Structure-based Computations

The biological membrane bilayer is impermeable to almost all polar or charged molecules. In order for the various solutes to cross this barrier, integral membrane proteins have evolved to provide a hydrophilic environment within the membrane that can bind and translocate these solutes into or out of the cell, often against their electrochemical gradient. These transporters are conventionally classified into three classes on the basis of the energy source used for transport: (1) primary active transporters rely on light, hydrolysis of ATP or redox reactions, (2) secondary active transporters require the electrochemical gradient of ions across the membrane to power the “uphill” translocation of the substrate, and (3) precursor/product antiporters exchange one molecule with its metabolic product independent of another source of energy. A major family of secondary transporters involves sodium(and less often proton-) dependent symporters that couple the energy-costly translocation of the solute into the cell to that of sodium down its electrochemical gradient. These sodium-coupled transporters are found in all species and participate in a myriad biological functions, e.g. maintenance of efficient neurotransmission, absorption of nutrients in the intestine, regulation of pH and cytoplasmic [Na+]7,8 and osmoregulation are only some of their physiological functions. Of particular interest among sodium-coupled symporters are two families: the dicarboxylate/ amino-acid:cation symporters (DAACS) and the neurotransmitter sodium symporters (NSS). The DAACS and NSS keep the extracellular (EC) neurotransmitter concentrations sufficiently low at the synaptic cleft, which enables postsynaptic receptors to detect signaling by the presynaptic nerve cell in the form of exocytotically released transmitters (Figure 1). The DAACS and NSS are key elements in the termination of the synaptic action of neurotransmitters, which is accomplished by diffusion and re-uptake of neurotransmitters into neuronal or glial cells; the single exception in this regard involves acetylcholine-mediated signal transmission. FA