Editing Uniporter (section)

== Types ==
=== Glucose transporter (GLUTs) ===

The glucose transporter (GLUTs) is a type of uniporter responsible for the [[facilitated diffusion]] of glucose molecules across cell membranes.<ref name="Olson AL">{{cite journal |vauthors=Olson AL, Pessin JE |title=Structure, function, and regulation of the mammalian facilitative glucose transporter gene family |journal=Annu Rev Nutr |volume=16 |issue= |pages=235–56 |date=1996 |pmid=8839927 |doi=10.1146/annurev.nu.16.070196.001315 }}</ref>[[Glucose]] is a vital energy source for most living cells, however, due to its large size, it cannot freely move through the cell membrane.<ref name="Navale AM">{{cite journal |vauthors=Navale AM, Paranjape AN |title=Glucose transporters: physiological and pathological roles |journal=Biophys Rev |volume=8 |issue=1 |pages=5–9 |date=March 2016 |pmid=28510148 |pmc=5425736 |doi=10.1007/s12551-015-0186-2 }}</ref> The glucose transporter is specialized in transporting glucose specifically across the membrane. The GLUT proteins have several types of [[Protein isoform|isoforms]], each distributed in different [[Tissue (biology)|tissues]] and exhibiting different [[Chemical kinetics|kinetic properties.]]<ref name="Navale AM" />
[[File:Glucose-6-phosphatase system.svg|thumb|Glucose transporter]]
GLUTs are [[integral membrane protein]]s composed of [[Alpha helix|12 α-helix membrane spanning regions]].<ref name="Navale AM" /> The GLUT proteins are encoded by the [[SLA2|SLC2 genes]] and categorized into three classes based on [[Protein primary structure|amino acid sequence]] similarity.<ref>{{cite journal |vauthors=Mueckler M, Thorens B |title=The SLC2 (GLUT) family of membrane transporters |journal=Mol Aspects Med |volume=34 |issue=2–3 |pages=121–38 |date=2013 |pmid=23506862 |pmc=4104978 |doi=10.1016/j.mam.2012.07.001 }}</ref> Humans have been found to express fourteen GLUT proteins. Class I GLUTs include [[GLUT1]], one of the most studied isoforms, and [[GLUT2]].<ref name="Navale AM" /> GLUT1 is found in various tissues like the [[red blood cell]]s, [[brain]], and [[Blood–brain barrier|blood-brain barrier]] and is responsible for basal [[glucose uptake]].<ref name="Navale AM" /> GLUT2 is predominantly found in the [[liver]], [[pancreas]], and [[small intestine]]s.<ref name="Navale AM" /> It plays an important role in insulin secretion from [[Beta cell|pancreatic beta cells]]. Class II includes the [[GLUT3]] and [[GLUT4]].<ref name="Navale AM" /> GLUT3, primarily found in the brain, [[neuron]]s and [[placenta]], has a high  [[Affinity electrophoresis|affinity]] for glucose in facilitating glucose uptake into neurons.<ref name="Navale AM" /> [[GLUT4]] plays a role in insulin-regulated glucose uptake and is mainly found in insulin-sensitive tissues such as muscle and [[adipose tissue]].<ref name="Navale AM" /> Class III includes [[GLUT5]], found in the [[small intestine]], [[kidney]], [[Testicle|testes]], and [[skeletal muscle]].<ref name="Navale AM" /> Unlike the other GLUTs, GLUT5 specifically transports [[fructose]] rather than glucose.<ref name="Navale AM" />

Glucose transporters allow glucose molecules to move down their concentration gradient from areas of high glucose concentration to areas of low concentration. This process often involves bringing glucose from the [[extracellular space]] or [[blood]] into the cell. The concentration gradient set up by glucose concentrations fuels the process without the need for ATP.<ref>{{cite journal |vauthors=Carruthers A |title=Facilitated diffusion of glucose |journal=Physiol Rev |volume=70 |issue=4 |pages=1135–76 |date=October 1990 |pmid=2217557 |doi=10.1152/physrev.1990.70.4.1135 }}</ref>

When glucose binds to the glucose transporter, the protein channels change shape and undergo a conformational change to transport the glucose across the membrane. Once the glucose unbinds, the protein returns to its original shape. The glucose transporter is essential for carrying out physiological processes that require high energy demands in the brain, muscles, and kidneys by providing an adequate amount of energy substrate for [[metabolism]]. [[Diabetes]], an example of a condition that involves glucose metabolism, highlights the importance of the regulation of glucose uptake in disease management.<ref>{{cite journal |vauthors=Jiang S, Young JL, Wang K, Qian Y, Cai L |title=Diabetic&#x2011;induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review) |journal=Mol Med Rep |volume=22 |issue=2 |pages=603–611 |date=August 2020 |pmid=32468027 |pmc=7339764 |doi=10.3892/mmr.2020.11175 }}</ref>

=== Mitochondrial {{chem2|Ca(2+)}} uniporter (MCU) ===
The '''mitochondrial calcium uniporter''' (MCU) is a protein complex located in the inner mitochondrial matrix that functions to take up calcium ions (Ca2+) into the [[Mitochondrial matrix|matrix]] from the [[cytoplasm]].<ref name="De Stefani D">{{cite journal |vauthors=De Stefani D, Patron M, Rizzuto R |title=Structure and function of the mitochondrial calcium uniporter complex |journal=Biochim Biophys Acta |volume=1853 |issue=9 |pages=2006–11 |date=September 2015 |pmid=25896525 |pmc=4522341 |doi=10.1016/j.bbamcr.2015.04.008 }}</ref> The transport of calcium ions is specifically used in cellular function for regulating energy production in the mitochondria, cytosolic [[calcium signaling]], and [[cell death]]. The uniporter becomes activated when cytoplasmic levels of calcium rise above 1 uM.<ref name="De Stefani D" />

The [[Mitochondrial calcium uniporter|MCU complex]] comprises 4 parts: the port-forming subunits, regulatory subunits [[MICU1 (gene)|MICU1]] and MICU2, and an auxiliary subunit, EMRE.<ref name="D'Angelo D">{{cite journal |vauthors=D'Angelo D, Rizzuto R |title=The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases |journal=Biomolecules |volume=13 |issue=9 |date=August 2023 |page=1304 |pmid=37759703 |pmc=10526485 |doi=10.3390/biom13091304 |doi-access=free }}</ref> These subunits work together to regulate the uptake of calcium in the mitochondria. Specifically, the EMRE subunit functions for the transport of calcium, and the MICU subunit functions in tightly regulating the activity of MCU to prevent the overload of calcium concentrations in the cytoplasm.<ref name="D'Angelo D" /> Calcium is fundamental for signaling pathways in cells, as well as for cell death pathways.<ref name="D'Angelo D" /> The function of the mitochondrial uniporter is critical for maintaining cellular [[homeostasis]].

The MICU1 and MICU2 subunits are a [[Protein dimer|heterodimer]] connected by a [[Disulfide|disulfide bridge]].<ref name="De Stefani D" /> When there are high levels of cytoplasmic calcium, the MICU1-MICU2 heterodimer undergoes a [[conformational change]].<ref name="De Stefani D" /> The heterodimer subunits have cooperative activation, which means {{chem2|Ca(2+)}} binding to one MICU subunit in the heterodimer induces a conformational change on the other MICU subunits. The uptake of calcium is balanced by the [[sodium-calcium exchanger]].<ref name="D'Angelo D" />

=== Large neutral amino acid transporter (LAT1) ===
[[File:Protein SLC3A2 PDB 2dh2.png|thumb|SLC3 protein coding gene for LAT1]]
The '''L-type amino acid transporter (LAT1)''' is a uniporter that mediates the transport of [[Neutral amino acid transporter A|neutral amino acids]] like [[Tryptophan|L-tryptophan]], [[leucine]], [[histidine]], [[proline]], [[alanine]], etc.<ref name="Häfliger P">{{cite journal |vauthors=Häfliger P, Charles RP |title=The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer |journal=Int J Mol Sci |volume=20 |issue=10 |date=May 2019 |page=2428 |pmid=31100853 |pmc=6566973 |doi=10.3390/ijms20102428 |doi-access=free }}</ref> [[CD98|LAT1]] favors the transport of amino acids with large branched or [[Amino acid|aromatic side chains]]. The amino acid transporter functions to move essential amino acids into the [[intestinal epithelium]], [[placenta]], and [[Blood–brain barrier|blood-brain barrier]] for cellular processes such as metabolism and cell signaling.<ref name="Bhutia YD">{{cite journal |vauthors=Bhutia YD, Mathew M, Sivaprakasam S, Ramachandran S, Ganapathy V |title=Unconventional Functions of Amino Acid Transporters: Role in Macropinocytosis (SLC38A5/SLC38A3) and Diet-Induced Obesity/Metabolic Syndrome (SLC6A19/SLC6A14/SLC6A6) |journal=Biomolecules |volume=12 |issue=2 |date=January 2022 |page=235 |pmid=35204736 |pmc=8961558 |doi=10.3390/biom12020235 |doi-access=free }}</ref> The transporter is of particular significance in the [[central nervous system]] as it provides the necessary amino acids for protein synthesis and [[Neurotransmitter|neurotransmitter production]] in brain cells.<ref name="Bhutia YD" /> [[Aromatic amino acid]]s like [[phenylalanine]] and [[tryptophan]] are precursors for neurotransmitters like [[dopamine]], [[serotonin]], and [[norepinephrine]].<ref name="Bhutia YD" />

LAT1 is a membrane protein of the [[SLC7A14|SLC7]] family of transporters and works in conjunction with the [[Solute carrier family|SLC3 family]] member [[4F2 cell-surface antigen heavy chain|4F2hc]] to form a [[Protein dimer|heterodimeric]] complex known as the 4F2hc complex.<ref name="Häfliger P" /> The heterodimer consists of a light chain and a heavy chain [[Covalent bond|covalently bonded]] by a [[disulfide bond]]. The light chain is the one that carries out transport, while the heavy chain is needed to stabilize the dimer.<ref name="Häfliger P" />

There is some controversy over whether LAT1 is an uniporter or an [[antiporter]]. The transporter has uniporter characteristics of transporting amino acids into cells in a unidirectional manner down the concentration gradient. However, recently it has been found that the transporter has antiporter characteristics of exchanging neutral amino acids for abundant intracellular amino acids.<ref>{{cite journal |vauthors=Singh N, Ecker GF |title=Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1 |journal=Int J Mol Sci |volume=19 |issue=5 |date=April 2018 |page=1278 |pmid=29695141 |pmc=5983779 |doi=10.3390/ijms19051278 |doi-access=free }}</ref>  Over-expression of LAT1 has been found in human [[cancer]] and is associated with playing a role in cancer metabolism.<ref>{{cite journal |vauthors=Kanai Y |title=Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics |journal=Pharmacol Ther |volume=230 |issue= |pages=107964 |date=February 2022 |pmid=34390745 |doi=10.1016/j.pharmthera.2021.107964 }}</ref>

=== Equilibrative nucleoside transporters (ENTs) ===
The '''nucleoside transporters''', or '''equilibrative nucleoside transporters''', are uniporters that transport [[nucleoside]]s, [[nucleobase]]s, and [[Pharmacology|therapeutic drugs]] across the cell membrane.<ref name="Boswell">{{cite journal |vauthors=Boswell-Casteel RC, Hays FA |title=Equilibrative nucleoside transporters-A review |journal=Nucleosides Nucleotides Nucleic Acids |volume=36 |issue=1 |pages=7–30 |date=January 2017 |pmid=27759477 |pmc=5728162 |doi=10.1080/15257770.2016.1210805 }}</ref> Nucleosides serve as building blocks for [[Nucleic acid|nucleic acid synthesis]] and are key components for energy metabolism in creating [[Adenosine triphosphate|ATP]]/ [[Guanosine triphosphate|GTP]].<ref name="Hollenstein M">{{cite journal |vauthors=Hollenstein M |title=Nucleoside triphosphates--building blocks for the modification of nucleic acids |journal=Molecules |volume=17 |issue=11 |pages=13569–91 |date=November 2012 |pmid=23154273 |pmc=6268876 |doi=10.3390/molecules171113569 |doi-access=free }}</ref> They also act as ligands for [[Receptors, amino acid|purinergic receptors]] such as [[adenosine]] and [[inosine]]. ENTs allow the transport of nucleosides down their concentration gradient. They also have the ability to deliver nucleoside analogs to intracellular targets for the treatment of [[Neoplasm|tumors]] and viral infections.<ref name="Hollenstein M" />

ENTs are part of the [[Major facilitator superfamily|Major Facilitator Superfamily (MFS)]] and are suggested to transport nucleosides using a clamp-and-switch model.<ref name="Hollenstein M" /> In this model, the substrate first binds to the transporter, which leads to a conformational change that forms an occluded state (clamp). Then, the transporter switches to face the other side of the membrane and releases the bound substrate (switching).<ref name="Hollenstein M" />

ENTs have been found in [[protozoa]] and mammals. In humans, they have been discovered as ENT3 (hENT1-3) and [[ENT4]] (hENT4) transporters.<ref name="Boswell" /> ENTs are expressed across all tissue types, but certain ENT proteins have been found to be more abundant in specific tissues. hENT1 is found mostly in the [[adrenal gland]]s, [[ovary]], [[stomach]] and [[small intestine]]s.<ref name="Boswell" /> hENT2 is expressed mostly in neurological tissues and small parts of the [[skin]], placenta, [[Bladder|urinary bladder]], [[Cardiac muscle|heart muscle]] and [[gallbladder]].<ref name="Boswell" /> hENT3 is expressed highly in the [[cerebral cortex]], [[Lateral ventricles|lateral ventricle]], [[ovary]] and [[adrenal gland]].<ref name="Boswell" /> hENT4 is more commonly known as the [[Plasma membrane monoamine transporter|plasma membrane monoamine transporter (PMAT)]], as it facilitates the movement of organic [[Ion|cations]] and biogenic [[amine]]s across the membrane.<ref name="Boswell" />