Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Abstract

Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

“…ENT1 and ENT2 have a fairly ubiquitous cell surface expression and are capable of mediating adenine (and hypoxanthine) transport across the blood brain barrier [126][127][128][129]. It is also likely that allopurinol enters the brain in this way, given its closely related structure to hypoxanthine (Fig.…”

Regulation of adenosine levels during cerebral ischemia

“…Transporter-mediated cellular influx or efflux of adenosine attenuates or enhances, respectively, extracellular levels of adenosine and adenosine receptor activity. Two families of nucleoside transporters have been described, equilibrative and concentrative, with the former expressed by all cell types and the latter localized primarily in absorptive tissues such as epithelial cells [13] . Concentrative nucleoside transporters (CNTs) are members of the solute carrier 28 (SLC28) gene family.…”

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…NBTI partially inhibits ENTs at the nM concentration range ("es": equilibrative, NBTI sensitive type of ENTs, e.g., ENT1), whereas NBTI insensitive transporters are inhibited by NBTI only at the m M concentration range ("ei": equilibrative, NBTI insensitive type of ENTs, e.g., ENT2). The concentrative nucleoside transporter family (CNT transporters; unidirectional, sodium-dependent) includes six CNT transporter types (N1-N6) that are classi fi ed based on the types of nucleosides transported and sodium transport coupling Barnes et al 2006 ;Jennings et al 2001 ;Parkinson et al 2011 ;Pennycooke et al 2001 ;Ritzel et al 2001 ) .…”

“…In addition, nucleosides participate in physiological and pathophysiological processes in the brain, such as the regulation of sleep and memory, epilepsy, Parkinson's disease, and Alzheimer's disease Huang et al 2011 ;Lopes et al 2011 ;Sperlágh and Vizi 2011 ) . Increasingly, nucleoside derivatives and uptake or metabolic inhibitors are being used in clinical or preclinical drug development for the treatment of different diseases, ranging from viral infections to neurodegenerative disorders (Boison 2011 ;Lopes et al 2011 ;Parkinson et al 2011 ) .…”