Abstract
Large amino acid transporter 1 (LAT1), also known as SLC7A5, is an essential amino acid transporter that forms a heterodimeric complex with the glycoprotein cell-surface antigen heavy chain (4F2hc (CD98, SLC3A2)). Within nociceptive pathways, LAT1 is expressed in the dorsal root ganglia and spinal cord. Although LAT1 expression is upregulated following spinal cord injury, little is known about LAT1 in neuropathic pain. To date, only circumstantial evidence supports LAT1/4F2hc’s role in pain. Notably, LAT1′s expression and regulation link it to key cell types and pathways implicated in pain. Transcriptional regulation of LAT1 expression occurs via the Wnt/frizzled/β-catenin signal transduction pathway, which has been shown to be involved in chronic pain. The LAT1/4F2hc complex may also be involved in pain pathways related to T- and B-cells. LAT1′s expression induces activation of the mammalian target of rapamycin (mTOR) signaling axis, which is involved in inflammation and neuropathic pain. Similarly, hypoxia and cancer induce activation of hypoxia-inducible factor 2 alpha, promoting not only LAT1′s expression but also mTORC1′s activation. Perhaps the strongest evidence linking LAT1 to pain is its interactions with key voltage-gated ion channels connected to nociception, namely the voltage-gated potassium channels Kv1.1 and Kv1.2 and the voltage-gated sodium channel Nav1.7. Through functional regulation of these channels, LAT1 may play a role in governing the excitatory to inhibitory ratio which is altered in chronic neuropathic pain states. Remarkably, the most direct role for LAT1 in pain is to mediate the influx of gabapentin and pregabalin, two first-line neuropathic pain drugs, that indirectly inhibit high voltage-activated calcium channel auxiliary subunit α2δ-1. In this review, we discuss the expression, regulation, relevant signaling pathways, and protein interactions of LAT1 that may link it to the development and/or maintenance of pain. We hypothesize that LAT1 expressed in nociceptive pathways may be a viable new target in pain.
Highlights
Large amino acid transporters (LATs) import essential amino acids into cells
The most abundant, Large amino acid transporter 1 (LAT1), is a Na+-independent exchanger of large neutral amino acids (Kanai et al, 1998; Segawa et al, 1999). It is linked by a disulfide bond (Kanai et al, 1998; Verrey et al, 2000) and polar interactions (Yan et al, 2019) to 4F2 cell-surface antigen heavy chain (4F2hc), known as SLC3A2. 4F2hc is a glycoprotein that allows the formation of stable transporter complexes for their localization to the plasma membrane where they are functional (Kanai et al, 1998; Yan et al, 2019)
Recruitment of Wnt signaling stimulated the production of the proinflammatory cytokines interleukin 18 (IL-18) and tumor necrosis factor -alpha (TNF-α), as well as the N-methyl-D-aspartate receptor subunit NR2B in the spinal cord (Zhang et al, 2013b), which play a crucial role in pain pathways. These findings suggest that LAT1′s transcriptional regulation by Wnt’s signalling pathway might be a crucial mechanism underlying the pathogenesis of inflammation and neuropathic pain
Summary
Large amino acid transporters (LATs) import essential amino acids into cells. There are four types of LATs, known as Solute Carrier Family 7 Member 5 (SLC7A5 or LAT1), SLC7A8 (LAT2), SLC43A1 (LAT3), and SLC43A2 (LAT4) (Wang and Holst, 2015). The most abundant, LAT1, is a Na+-independent exchanger of large neutral amino acids (Kanai et al, 1998; Segawa et al, 1999). It is linked by a disulfide bond (Kanai et al, 1998; Verrey et al, 2000) and polar interactions (Yan et al, 2019) to 4F2 cell-surface antigen heavy chain (4F2hc), known as SLC3A2.
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