PMID- 32715162
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231111
IS  - 2452-073X (Electronic)
IS  - 2452-073X (Linking)
VI  - 8
DP  - 2020 Aug-Dec
TI  - Putative roles of SLC7A5 (LAT1) transporter in pain.
PG  - 100050
LID - 10.1016/j.ynpai.2020.100050 [doi]
LID - 100050
AB  - 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/beta-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 alpha2delta-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.
CI  - (c) 2020 Published by Elsevier Inc.
FAU - Alles, Sascha R A
AU  - Alles SRA
AD  - Department of Anesthesiology and Critical Care Medicine, University of New Mexico 
      School of Medicine, United States.
FAU - Gomez, Kimberly
AU  - Gomez K
AD  - Department of Pharmacology, University of Arizona, United States.
FAU - Moutal, Aubin
AU  - Moutal A
AD  - Department of Pharmacology, University of Arizona, United States.
FAU - Khanna, Rajesh
AU  - Khanna R
AD  - Department of Pharmacology, University of Arizona, United States.
AD  - Department of Anesthesiology, College of Medicine, The University of Arizona, 
      Tucson, AZ 85724, United States.
AD  - BIO5 Institute, University of Arizona, 1657 East Helen Street Tucson, AZ 85719, 
      United States.
AD  - Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ 85721, 
      United States.
AD  - Regulonix Holding Inc., Tucson, AZ, United States.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20200630
PL  - United States
TA  - Neurobiol Pain
JT  - Neurobiology of pain (Cambridge, Mass.)
JID - 101705141
PMC - PMC7369351
OTO - NOTNLM
OT  - Gabapentinoids
OT  - Inflammation
OT  - Ion channels
OT  - LAT1
OT  - Neuropathic pain
OT  - mTOR
COIS- R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids 
      drugs for chronic pain. In addition, R. Khanna has patents US10287334 and 
      US10441586 issued to Regulonix LLC. The remaining authors declare that they have 
      no known competing financial interests or personal relationships that could have 
      appeared to influence the work reported in this paper.
EDAT- 2020/07/28 06:00
MHDA- 2020/07/28 06:01
PMCR- 2020/06/30
CRDT- 2020/07/28 06:00
PHST- 2020/06/01 00:00 [received]
PHST- 2020/06/23 00:00 [revised]
PHST- 2020/06/24 00:00 [accepted]
PHST- 2020/07/28 06:00 [entrez]
PHST- 2020/07/28 06:00 [pubmed]
PHST- 2020/07/28 06:01 [medline]
PHST- 2020/06/30 00:00 [pmc-release]
AID - S2452-073X(20)30008-8 [pii]
AID - 100050 [pii]
AID - 10.1016/j.ynpai.2020.100050 [doi]
PST - epublish
SO  - Neurobiol Pain. 2020 Jun 30;8:100050. doi: 10.1016/j.ynpai.2020.100050. 
      eCollection 2020 Aug-Dec.