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Uniporters, also known assolute carriers orfacilitated transporters, are a type ofmembrane transport protein that passively transports solutes (small molecules, ions, or other substances) across a cell membrane.[1] It usesfacilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration.[2] Unlikeactive transport, it does not require energy in the form ofATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers.[3] Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.[4]
Uniporter carrier proteins work by binding to onemolecule orsubstrate at a time. Uniporter channels open in response to a stimulus and allow the free flow of specific molecules.[2]
There are several ways in which the opening of uniporter channels may be regulated:
Uniporters are found inmitochondria,plasma membranes andneurons.The uniporter in the mitochondria is responsible forcalcium uptake.[1] The calcium channels are used forcell signaling and triggeringapoptosis. The calcium uniporter transports calcium across the inner mitochondrial membrane and is activated when calcium rises above a certain concentration.[5] Theamino acid transporters function in transporting neutralamino acids forneurotransmitter production in brain cells.[6]Voltage-gated potassium channels are also uniporters found in neurons and are essential foraction potentials.[7] This channel is activated by a voltage gradient created bysodium-potassium pumps. When the membrane reaches a certain voltage, the channels open, whichdepolarizes the membrane, leading to anaction potential being sent down the membrane.[8]Glucose transporters are found in the plasma membrane and play a role in transportingglucose. They help to bring glucose from the blood or extracellular space into cells usually to be utilized for metabolic processes in generating energy.[9]
Uniporters are essential for certain physiological processes in cells, such as nutrient uptake, waste removal, and maintenance of ionic balance.
Early research in the 19th and 20th centuries onosmosis anddiffusion provided the foundation for understanding thepassive movement of molecules across cell membranes.[10]
In 1855, the physiologistAdolf Fick was the first to define osmosis and simple diffusion as the tendency forsolutes to move from a region of higher concentration to a lower concentration, also very well-known asFick's Laws of Diffusion.[11] Through the work ofCharles Overton in the 1890s, the concept that thebiological membrane issemipermeable became important to understanding the regulation of substances in and out of the cells.[11] The discovery offacilitated diffusion by Wittenberg and Scholander suggested thatproteins in the cell membrane aid in the transport of molecules.[12] In the 1960s - 1970s, studies on the transport ofglucose and other nutrients highlighted thespecificity andselectivity ofmembrane transport proteins.[13]
Technological advancements in biochemistry helped isolate and characterize these proteins from cell membranes. Genetic studies onbacteria andyeast identified genes responsible for encoding transporters. This led to the discovery ofglucose transporters (GLUT proteins), withGLUT1 being the first to be characterized.[14] Identification of gene families encoding various transporters, such assolute carrier (SLC) families, also advanced knowledge on uniporters and its functions.[14]
Newer research is focusing on techniques usingrecombinant DNA technology,electrophysiology and advanced imaging to understand uniporter functions. These experiments are designed toclone and express transporter genes in host cells to further analyze the three-dimensional structure of uniporters, as well as directly observe the movement of ions through proteins in real-time.[14] The discovery ofmutations in uniporters has been linked to diseases such asGLUT1 deficiency syndrome,cystic fibrosis,Hartnup disease,primary hyperoxaluria andhypokalemic periodic paralysis.[15]
The glucose transporter (GLUTs) is a type of uniporter responsible for thefacilitated diffusion of glucose molecules across cell membranes.[9]Glucose is a vital energy source for most living cells, however, due to its large size, it cannot freely move through the cell membrane.[16] The glucose transporter is specialized in transporting glucose specifically across the membrane. The GLUT proteins have several types ofisoforms, each distributed in differenttissues and exhibiting differentkinetic properties.[16]
GLUTs areintegral membrane proteins composed of12 α-helix membrane spanning regions.[16] The GLUT proteins are encoded by theSLC2 genes and categorized into three classes based onamino acid sequence similarity.[17] Humans have been found to express fourteen GLUT proteins. Class I GLUTs includeGLUT1, one of the most studied isoforms, andGLUT2.[16] GLUT1 is found in various tissues like thered blood cells,brain, andblood-brain barrier and is responsible for basalglucose uptake.[16] GLUT2 is predominantly found in theliver,pancreas, andsmall intestines.[16] It plays an important role in insulin secretion frompancreatic beta cells. Class II includes theGLUT3 andGLUT4.[16] GLUT3, primarily found in the brain,neurons andplacenta, has a highaffinity for glucose in facilitating glucose uptake into neurons.[16]GLUT4 plays a role in insulin-regulated glucose uptake and is mainly found in insulin-sensitive tissues such as muscle andadipose tissue.[16] Class III includesGLUT5, found in thesmall intestine,kidney,testes, andskeletal muscle.[16] Unlike the other GLUTs, GLUT5 specifically transportsfructose rather than glucose.[16]
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 theextracellular space orblood into the cell. The concentration gradient set up by glucose concentrations fuels the process without the need for ATP.[18]
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 formetabolism.Diabetes, an example of a condition that involves glucose metabolism, highlights the importance of the regulation of glucose uptake in disease management.[19]
Themitochondrial calcium uniporter (MCU) is a protein complex located in the inner mitochondrial matrix that functions to take up calcium ions (Ca2+) into thematrix from thecytoplasm.[20] The transport of calcium ions is specifically used in cellular function for regulating energy production in the mitochondria, cytosoliccalcium signaling, andcell death. The uniporter becomes activated when cytoplasmic levels of calcium rise above 1 uM.[20]
TheMCU complex comprises 4 parts: the port-forming subunits, regulatory subunitsMICU1 and MICU2, and an auxiliary subunit, EMRE.[21] 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.[21] Calcium is fundamental for signaling pathways in cells, as well as for cell death pathways.[21] The function of the mitochondrial uniporter is critical for maintaining cellularhomeostasis.
The MICU1 and MICU2 subunits are aheterodimer connected by adisulfide bridge.[20] When there are high levels of cytoplasmic calcium, the MICU1-MICU2 heterodimer undergoes aconformational change.[20] The heterodimer subunits have cooperative activation, which meansCa2+ binding to one MICU subunit in the heterodimer induces a conformational change on the other MICU subunits. The uptake of calcium is balanced by thesodium-calcium exchanger.[21]
TheL-type amino acid transporter (LAT1) is a uniporter that mediates the transport ofneutral amino acids likeL-tryptophan,leucine,histidine,proline,alanine, etc.[6]LAT1 favors the transport of amino acids with large branched oraromatic side chains. The amino acid transporter functions to move essential amino acids into theintestinal epithelium,placenta, andblood-brain barrier for cellular processes such as metabolism and cell signaling.[22] The transporter is of particular significance in thecentral nervous system as it provides the necessary amino acids for protein synthesis andneurotransmitter production in brain cells.[22]Aromatic amino acids likephenylalanine andtryptophan are precursors for neurotransmitters likedopamine,serotonin, andnorepinephrine.[22]
LAT1 is a membrane protein of theSLC7 family of transporters and works in conjunction with theSLC3 family member4F2hc to form aheterodimeric complex known as the 4F2hc complex.[6] The heterodimer consists of a light chain and a heavy chaincovalently bonded by adisulfide bond. The light chain is the one that carries out transport, while the heavy chain is needed to stabilize the dimer.[6]
There is some controversy over whether LAT1 is an uniporter or anantiporter. 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.[23] Over-expression of LAT1 has been found in humancancer and is associated with playing a role in cancer metabolism.[24]
Thenucleoside transporters, orequilibrative nucleoside transporters, are uniporters that transportnucleosides,nucleobases, andtherapeutic drugs across the cell membrane.[25] Nucleosides serve as building blocks fornucleic acid synthesis and are key components for energy metabolism in creatingATP/GTP.[26] They also act as ligands forpurinergic receptors such asadenosine andinosine. 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 oftumors and viral infections.[26]
ENTs are part of theMajor Facilitator Superfamily (MFS) and are suggested to transport nucleosides using a clamp-and-switch model.[26] 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).[26]
ENTs have been found inprotozoa and mammals. In humans, they have been discovered as ENT3 (hENT1-3) andENT4 (hENT4) transporters.[25] 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 theadrenal glands,ovary,stomach andsmall intestines.[25] hENT2 is expressed mostly in neurological tissues and small parts of theskin, placenta,urinary bladder,heart muscle andgallbladder.[25] hENT3 is expressed highly in thecerebral cortex,lateral ventricle,ovary andadrenal gland.[25] hENT4 is more commonly known as theplasma membrane monoamine transporter (PMAT), as it facilitates the movement of organiccations and biogenicamines across the membrane.[25]
Uniporters work to transport molecules or ions bypassive transport across a cell membrane down itsconcentration gradient.
Upon binding and recognition of a specific substrate molecule on one side of the uniporter membrane, aconformational change is triggered in the transporter protein.[27] This causes the transporter protein to change its three-dimensional shape, which ensures the substrate molecule is captured within the transporter proteins structure. The conformational change leads to the translocation of the substrate across the membrane onto the other side.[27] On the other side of the membrane, the uniporter undergoes another conformational change in the release of the substrate molecule. The uniporter returns to its original conformation to bind another molecule for transport.[27]
Unlikesymporters andantiporters, uniporters transport one molecule/ion in a single direction based on the concentration gradient.[28] The entire process depends on the substrate's concentration difference across the membrane to be the driving force for the transport by uniporters.[28] Cellular energy in the form ofATP is not required for this process.[28]
Uniporters play an essential role in carrying out various cellular functions. Each uniporter is specialized to facilitate the transport of a specific molecule or ion across the cell membrane. Examples of a few of the physiological roles uniporters aid in include:[29]
Mutations in genes encoding uniporters lead to dysfunctional transporter proteins being formed. This loss of function in uniporters causes disruption in cellular function which leads to variousdiseases and disorders.
| Gene with mutation | Disease | Result of disease |
|---|---|---|
| Mutations in theSLC2A1 gene which encode glucose transporters (GLUTs)[32] | GLUT1 Deficiency Syndrome[32] | Impaired glucose transport across the blood-brain barriers, and neurological symptoms such as seizures, development delay, and movement disorders[33] |
| Mutations in theCFTR gene encodingion channels[32] | Cystic Fibrosis[32] | Problems with breathing and digestion due to thick mucus forming; affects multiple organs, primarily the lungs and digestive system[33] |
| Mutation inKCNA1 gene encodingpotassium channels[32] | Hypokalemic Periodic Paralysis[32] | Periodic muscle weakness; associated with low potassium levels due to altered transport activity[33] |
| Mutations in theSLC6A19 gene encoding amino acid transporter[32] | Hartnup Disease[32] | Impaired absorption of certain amino acid in the intestines and kidneys[33] |
| Mutations in theAGXT gene encoding peroxisomal membrane transporter[32] | Primary Hyperoxaluria[32] | Metabolic disease; Leads to accumulation of oxalate in causing kidney stone and damage[33] |
