Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases.

Abstract

It has become widely acknowledged that astrocytes play essential roles in maintaining physiological central nervous system (CNS) activities. Astrocytes fulfill their roles partly through the manipulation of their plasma membrane transporter functions, and therefore these transporters have been regarded as promising drug targets for various CNS diseases. A representative example is excitatory amino acid transporter 2 (EAAT2), which works as a critical regulator of excitatory signal transduction through its glutamate uptake activity at the tripartite synapse. Thus, enhancement of EAAT2 functionality is expected to accelerate glutamate clearance at synapses, which is a promising approach for the prevention of over-excitation of glutamate receptors. In addition to such well-known astrocyte-specific transporters, cumulative evidence suggests that multi-specific organic ion transporters (i.e., organic cation/anion transporters [OCTs/OATs], carnitine/organic cation transporters [OCTNs], and organic anion transporting polypeptides [OATPs]) are also functionally expressed in astrocytes. Even though identification and characterization of their physiological/pathophysiological roles in astrocytes are in the initial stage, the findings obtained so far indicate that OCT3 and plasma membrane monoamine transporter are significantly involved in the clearance of biogenic amine neurotransmitters in the synaptic cleft, and that OCTN2 and OATP1C1 provide a cellular entry gate for carnitine/acetyl-L-carnitine and thyroxine, respectively. Therefore, organic ion transporters, including those mentioned above, are expected to become emerging pharmacological targets for various CNS diseases. With such expectations in mind, this review will briefly summarize the functional expression of organic ion transporters in astrocytes.