Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

Published on Nov 9, 2020in eLife8.146
· DOI :10.7554/ELIFE.54916
Shawn M. Lamothe8
Estimated H-index: 8
(U of A: University of Alberta),
Nazlee Sharmin3
Estimated H-index: 3
(U of A: University of Alberta)
+ 5 AuthorsHarley T. Kurata21
Estimated H-index: 21
(U of A: University of Alberta)
Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter Slc7a5. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement ('disinhibition') with holding potentials more negative than -120 mV. Knockdown of endogenous Slc7a5 leads to larger Kv1.1 currents and strongly attenuates the disinhibition effect, suggesting that Slc7a5 regulation of Kv1.1 involves channel inhibition that can be reversed by supraphysiological hyperpolarizing voltages. We investigated chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5, and localize a specific position in S1 with prominent effects on Slc7a5 sensitivity. Overall, our study highlights multiple Slc7a5-sensitive Kv1 subunits, and identifies the voltage-sensing domain as a determinant of Slc7a5 modulation of Kv1 channels.
#1Sascha R.A. Alles (UNM: University of New Mexico)H-Index: 8
#2Kimberly Gomez (UA: University of Arizona)H-Index: 6
Last. Rajesh KhannaH-Index: 40
view all 4 authors...
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 ...
#1Shawn M. Lamothe (U of A: University of Alberta)H-Index: 8
#2Harley T. Kurata (U of A: University of Alberta)H-Index: 21
The voltage-gated potassium channel Kv1.2 plays a pivotal role in neuronal excitability and is regulated by a variety of known and unknown extrinsic factors. The canonical accessory subunit of Kv1.2, Kvbeta, promotes N-type inactivation and cell surface expression of the channel. We recently reported that a neutral amino acid transporter, Slc7a5, alters the function and expression of Kv1.2. In the current study, we investigated the effects of Slc7a5 on Kv1.2 in the presence of Kvbeta1.2 subunits...
#1Motoyasu Satou (U of A: University of Alberta)H-Index: 2
#2Jason Wang (U of A: University of Alberta)H-Index: 1
Last. Toru Tateno (U of A: University of Alberta)H-Index: 15
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Abstract Pituitary tumors (PTs) can cause significant mortality and morbidity due to limited therapeutic options. L-type amino acid transporters (LATs), in particular, the LAT1 isoform, is expressed in a variety of tumor cells. Pharmacological inhibition or genetic ablation of LAT1 can suppress leucine transport into cancer cells, resulting in suppression of cancer cell growth. However, roles of LAT1 in PTs have not been elucidated. Therefore, we assessed LAT1 expression in PTs and evaluated a L...
#1Julia M. Marchingo (Dund.: University of Dundee)H-Index: 8
#2Linda V Sinclair (Dund.: University of Dundee)H-Index: 23
Last. Doreen A. Cantrell (Dund.: University of Dundee)H-Index: 92
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T cells are white blood cells that form an important part of our immune defence, acting to attack disease-causing microbes and cancer and directing other immune cells to help in this fight. T cells spend most of their time in a resting state, small and inactive, but when an infection strikes, they transform into large, active 'effector' cells. This change involves a dramatic increase in protein production, accompanied by high energy demands. To fully activate, T cells need to boost their metabol...
#1Nadège Poncet (Dund.: University of Dundee)H-Index: 3
#2Pamela A. Halley (Dund.: University of Dundee)H-Index: 8
Last. Kate G. Storey (Dund.: University of Dundee)H-Index: 36
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Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5/Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5‐null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5‐null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylat...
The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked heterodimer with CD98 heavy chain (CD98hc, 4F2hc or SLC3A2), but the mechanism of assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1–CD98hc heterodimer at 3.3-A resolution. LAT1 features a canonical Leu T-fold and exhibits an unusual loop str...
#1Madelyn J. Abraham (U of O: University of Ottawa)H-Index: 1
#2Kayla L. Fleming (U of O: University of Ottawa)H-Index: 1
Last. Richard Bergeron (Ottawa Hospital Research Institute)H-Index: 25
view all 5 authors...
: Expression of Kv1.2 within Kv1.x potassium channel complexes is critical in maintaining appropriate neuronal excitability and determining the threshold for action potential firing. This is attributed to the interaction of Kv1.2 with a hitherto unidentified protein that confers bimodal channel activation gating, allowing neurons to adapt to repetitive trains of stimulation and protecting against hyperexcitability. One potential protein candidate is the sigma-1 receptor (Sig-1R), which regulates...
#1Joseph J. LebowitzH-Index: 7
#2Jose A. Pino (UF: University of Florida)H-Index: 9
Last. Habibeh KhoshboueiH-Index: 29
view all 10 authors...
: The dopamine transporter (DAT) regulates dopamine neurotransmission via reuptake of dopamine released into the extracellular space. Interactions with partner proteins alter DAT function and thereby dynamically shape dopaminergic tone important for normal brain function. However, the extent and nature of these interactions are incompletely understood. Here, we describe a novel physical and functional interaction between DAT and the voltage-gated K+ channel Kv2.1 (potassium voltage-gated channel...
#1Renhong Yan (THU: Tsinghua University)H-Index: 12
#2Xin Zhao (THU: Tsinghua University)H-Index: 7
Last. Qiang Zhou (Westlake University)H-Index: 14
view all 4 authors...
The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner1–3. LAT1, an antiporter of the amino acid–polyamine–organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as l-3,4-dihydroxyphenylalanine across membranes2–6. Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential ...
#1Clara Serrano-Novillo (University of Barcelona)H-Index: 5
#2Jesusa Capera (University of Barcelona)H-Index: 6
Last. Antonio Felipe (University of Barcelona)H-Index: 40
view all 6 authors...
Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication o...
Cited By1
#1Jared Tur (USF: University of South Florida)H-Index: 4
#2Kalyan C. Chapalamadagu (USF: University of South Florida)
Last. Srinivas M. Tipparaju (USF: University of South Florida)H-Index: 16
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Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the ...
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