Current Molecular Pharmacology - Volume 6, Issue 2, 2013

The solute carrier family 1 (SLC1) consists of two neutral amino acid transporters and five high-affinity excitatory amino acid transporters (EAAT1-5). EAATs are expressed in glial cells (EAAT1/GLAST and EAAT2/GLT-1), neurons (EAAT3/EAAC1 and EAAT4), and the retina (EAAT5), where they precisely regulate extracellular glutamate levels at both synaptic and extrasynaptic sites. EAATs play essential roles in the maintenance of normal excitatory synaptic transmission, protection of neurons from the excitotoxic action of excessive glutamate, and regulation of glutamatemediated neuroplasticity. Therefore, dysfunction of EAATs can cause abnormal excitatory synaptic transmission, neuronal excitotoxicity, and the exaggeration of neuroplasticity-based events. EAAT dysfunction has been implicated in a variety of neurodegenerative and neurological diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, ischemia, and epilepsy. Recent evidence suggests that abnormalities of EAATs contribute to the pathogenesis of psychiatric diseases and pathological pain. The present review will briefly discuss novel findings on the roles of EAATs in the pathogenesis of psychiatric diseases such as schizophrenia, mood disorders, and drug dependence/ addiction, and pathological pain, as well as the potential of EAATs as therapeutic targets.

SLC17A1 protein (NPT1) was the first identified member of the SLC17 phosphate transporter family, and is known to mediate Na+/inorganic phosphate (Pi) co-transport when expressed in Xenopus oocytes. Although this protein was suggested to be a renal polyspecific anion exporter, its transport properties were not well characterized. The clean biochemical approach revealed that proteoliposomes comprising purified NPT1 as the only protein source transport various organic anions such as urate, p-aminohippuric acid (PAH), and acetylsalicylic acid (aspirin) in a membrane potential (Δψ)-driven and Cl- -dependent manner. Human NPT1 carrying an SNP mutation, Thr269Ile, known to increase the risk of gout, exhibited 32% lower urate transport activity compared to the wild type protein, leading to the conclusion that NPT1 is the long searched for transporter responsible for renal urate excretion. In the present article, we summarized the history of identification of the urate exporter and its possible involvement in the dynamism of urate under physiological and pathological conditions.

Bile salt export pump (BSEP/ABCB11), a member of the family of ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and mediates the efficient biliary excretion of bile acid. The secretion of bile acid into bile by BSEP provides the primary osmotic driving force for bile flow generation. Intrahepatic cholestasis resulting from dysfunction of BSEP can be caused by a mutation in the gene encoding this protein or by acquired factors, such as the side effects of xenobiotics and drugs. In some pathophysiological states, inhibition of BSEP function is associated with its reduced expression on the canalicular membrane caused by impaired trafficking and sorting of BSEP. This fact has generated interest in better understanding the trafficking and sorting mechanism of BSEP. This review describes the molecular characteristics and physiological roles of BSEP, the trafficking and sorting machinery of BSEP, and the mechanisms responsible for disturbance of BSEP, which causes intrahepatic cholestasis.

Hypoxia-mediated regulation of N-methyl-D-aspartate (NMDA) receptor (NMDAR) is phenomenal. NMDAR is no doubt an intriguing paradoxical glutamate receptor (GluR) with versatile actions. GluRs play a pivotal role in brain physiology and pathophysiology under ischemia and oxygen deprivation, where NMDARs are major contributors. Activation of NMDARs is closely associated with the kinetics of intracellular calcium (Ca2+) release, a main player in neuronal cell death in the central nervous system (CNS). However, CNS exposure to hypoxia modulates NMDAR/Ca2+ physiology in such a way that there is a small window of operating neuroprotection, rather than the classical neuroinjurious effects manifested upon Ca2+ release. The NMDAR connection with hypoxia-inducible factor-1α (HIF-1α), a transcription factor considered master regulator of oxygen sensing mechanisms, is not well established in the CNS. However, scanning the literature yielded a wealth of NMDAR/hypoxia connection but that with HIF-1α is not prominent. It is worth mentioning that this is not a comprehensive review on the effect of hypoxia on NMDAR physiology, rather this synopsis sheds light on the putative mechanisms involving HIF-1α and NMDAR regulation. Understanding the evidence of this intimate connection and its ramifications may bear potential applications in unraveling hypoxia-mediated injury, neuronal cell death and, most importantly, adaptive, neuroprotective mechanisms to oxygen deprivation.