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Putative roles of SLC7A5 (LAT1) transporter in pain

Alles, Sascha R.A., Gomez, Kimberly, Moutal, Aubin, Khanna, Rajesh·2020·Neurobiology of Pain
DOI 10.1016/j.ynpai.2020.100050PMC PMC7369351
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Fig. 1 Expression of LAT1 and 4F2hc transcripts with LAT1 binding partners in DRG and spinal cord. Indicated gene expression values were extracted from the mousebrain.org database and then normalized to the maximum expression value for each gene for better visualization. (A) Scatter plot showing expression of Slc7a5 and Slc3a2 in DRG versus spinal cord. For this graph only, expression in the spinal cord was normalized to the maximum expression value in DRG. Gene expression for both was higher in DRG compared to spinal cord (Mann-Whitney, p < 0.0001). (B) Heatmap showing the normalized expression of Slc7a5 and Slc3a2 in DRG neuronal classes with functionally related genes Scn9a, Kcna1, Kcna2 and Cacna2d1. The neuronal markers Calca, P2rx3 and Nefh are shown to identify peptidergic, non-peptidergic and proprioceptor neurons respectively. (C) Heatmap showing the normalized expression of Slc7a5 and Slc3a2 in spinal cord neuronal classes with the functionally related genes Kcna1, Kcna2 and Cacna2d1. The markers of excitatory (Slc17a6) and inhibitory (Slc32a1) transmission are shown and the main neurotransmitter indicated according to the annotations curated from the database. Slc7a5: Large neutral amino acids transporter small subunit 1 (LAT1); Slc3a2: 4F2 cell-surface antigen heavy chain (4F2hc); Scn9a: Sodium channel protein type 9 subunit alpha (Nav1.7); Kcna1: Potassium voltage-gated channel subfamily A member 1 (Kv1.1); Kcna2: Potassium voltage-gated channel subfamily A member 2 (Kv1.2); Cacna2d1: Voltage-dependent calcium channel subunit alpha-2/delta-1 (α2δ-1); Calca: Calcitonin gene-related peptide 1 (CGRP); P2rx3: P2X purinoceptor 3 (P2X3R); Nefh: Neurofilament heavy polypeptide (NF200); Slc17a6: Vesicular glutamate transporter 2 (VGLUT2); Slc32a1: Vesicular inhibitory amino acid transporter (VGAT).
Fig. 1 Expression of LAT1 and 4F2hc transcripts with LAT1 binding partners in DRG and spinal cord. Indicated gene expression values were extracted from the mousebrain.org database and then normalized to the maximum expression value for each gene for better visualization. (A) Scatter plot showing expression of Slc7a5 and Slc3a2 in DRG versus spinal cord. For this graph only, expression in the spinal cord was normalized to the maximum expression value in DRG. Gene expression for both was higher in DRG compared to spinal cord (Mann-Whitney, p < 0.0001). (B) Heatmap showing the normalized expression of Slc7a5 and Slc3a2 in DRG neuronal classes with functionally related genes Scn9a, Kcna1, Kcna2 and Cacna2d1. The neuronal markers Calca, P2rx3 and Nefh are shown to identify peptidergic, non-peptidergic and proprioceptor neurons respectively. (C) Heatmap showing the normalized expression of Slc7a5 and Slc3a2 in spinal cord neuronal classes with the functionally related genes Kcna1, Kcna2 and Cacna2d1. The markers of excitatory (Slc17a6) and inhibitory (Slc32a1) transmission are shown and the main neurotransmitter indicated according to the annotations curated from the database. Slc7a5: Large neutral amino acids transporter small subunit 1 (LAT1); Slc3a2: 4F2 cell-surface antigen heavy chain (4F2hc); Scn9a: Sodium channel protein type 9 subunit alpha (Nav1.7); Kcna1: Potassium voltage-gated channel subfamily A member 1 (Kv1.1); Kcna2: Potassium voltage-gated channel subfamily A member 2 (Kv1.2); Cacna2d1: Voltage-dependent calcium channel subunit alpha-2/delta-1 (α2δ-1); Calca: Calcitonin gene-related peptide 1 (CGRP); P2rx3: P2X purinoceptor 3 (P2X3R); Nefh: Neurofilament heavy polypeptide (NF200); Slc17a6: Vesicular glutamate transporter 2 (VGLUT2); Slc32a1: Vesicular inhibitory amino acid transporter (VGAT).CC BY · PubMed Central
Fig. 2 The LAT1-4F2hc complex, its substrates and interactions with voltage-gated ion channels. (A) LAT1 mediates the influx of gabapentin (GBP) and pregabalin (PGB), which have been reported to bind to the α2δ-1 auxiliary subunits of high voltage-activated (HVA) Ca2+ channels. LAT1 also regulates mTOR/mTORC1 activity by controlling the influx of L-leucine. (B) The interaction of LAT1 with Kv1.1 or Kv1.2 causes the accumulation of these channels in a non-conducting state. LAT1 exists in a complex with Nav1.7 but whether this influences channel activity is unknown. LAT1-mediated influx of GBP and PGB allows the interaction of these drugs with α2δ-1 subunit which then inhibits the trafficking of HVA Ca2+ channels to the plasma membrane.
Fig. 2 The LAT1-4F2hc complex, its substrates and interactions with voltage-gated ion channels. (A) LAT1 mediates the influx of gabapentin (GBP) and pregabalin (PGB), which have been reported to bind to the α2δ-1 auxiliary subunits of high voltage-activated (HVA) Ca2+ channels. LAT1 also regulates mTOR/mTORC1 activity by controlling the influx of L-leucine. (B) The interaction of LAT1 with Kv1.1 or Kv1.2 causes the accumulation of these channels in a non-conducting state. LAT1 exists in a complex with Nav1.7 but whether this influences channel activity is unknown. LAT1-mediated influx of GBP and PGB allows the interaction of these drugs with α2δ-1 subunit which then inhibits the trafficking of HVA Ca2+ channels to the plasma membrane.CC BY · PubMed Central

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Metadata

Authors
Alles, S. R. A., Gomez, K., Moutal, A., & Khanna, R.
Venue
Neurobiology of Pain
Publisher
Elsevier BV
Published
2020-08
Volume
8
Pages
100050
ISSN
2452-073X
DOI
10.1016/j.ynpai.2020.100050
PMC
PMC7369351
Cited by
16
References
7
Language
en
Licence
Funders
  • University of New Mexico
  • National Institutes of Health (R01NS098772)
  • National Institute of Neurological Disorders and Stroke (R01DA042852)
  • National Institute on Drug Abuse

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