Biological membranes

Biological membranes are composed of lipid, protein and carbohydrate that exist in a fluid state. Biological membranes are the structures that define and control the composition of the space that they enclose. All membranes exist as dynamic structures whose composition changes throughout the life of a cell. In addition to the outer membrane that results in the formation of a typical cell (this membrane is often referred to as the plasma membrane), cells contain intracellular membranes that serve distinct functions in the formation of the various intracellular organelles, e.g. the nucleus and the mitochondria.

Activities of biological membranes

Although biological membranes contain various types of lipids and proteins, their distribution between the two different sides of the bilayer is asymmetric. As a general example the outer surface of the bilayer is enriched in phosphatidylethanolamine, whereas the intracellular surface is enriched in phosphatidylcholine. Carbohydrates, whether attached to lipid or protein, are almost exclusively found on the external surfaces of membranes. The asymmetric distribution of lipids and proteins in membranes results in the generation of highly specialized sub-domains within membranes. In addition, there are highly specialized membrane structures such as the endoplasmic reticulum (ER), the Golgi apparatus and vesicles. The most important vesicles are those that contain secreted factors. Membrane bound proteins (e.g. growth factor receptors) are processed as they transit through the ER to the Golgi apparatus and finally to the plasma membrane. As these proteins transit to the surface of the cell they undergo a series of processing events that includes glycosylation.

The vesicles that pinch off from the Golgi apparatus are termed coated vesicles. The membranes of coated vesicles are surrounded by specialized scaffolding proteins that will interact with the extracellular environment. There are three major types of coated vesicles that are characterized by their protein coats. Clathrin-coated vesicles contain the protein clathrin and are involved in transmembrane protein, GPI-linked protein and secreted protein transit to the plasma membrane. COPI (COP = coat protein) forms the surface of vesicles involved in the transfer of proteins between successive Golgi compartments. COPII forms the surface of vesicles that transfer proteins from the ER to the Golgi apparatus. Clathrin-coated vesicles are also involved in the process of endocytosis such as occurs when the LDL receptor binds plasma LDLs for uptake by the liver. The membrane location of these types of receptors is called a clathrin-coated pit.

In addition, certain cells have membrane compositions that are unique to one surface of the cell versus the other. For instance epithelial cells have a membrane surface that interacts with the lumenal cavity of the organ and another that interacts with the surrounding cells. The membrane surface of cells that interacts with lumenal contents is referred to as the apical surface or domain, the rest of the membrane is referred to as the basolateral surface or domain. The apical and basolateral domains do not intermix and contain different compositions of lipid and protein.

Most eukaryotic cells are in contact with their neighboring cells and these interactions are the basis of the formation of organs. Cells that abut one another are in metabolic contact which is brought about by specialized tubular particles called gap junctions. Gap junctions are intercellular channels and their presence allows whole organs to be continuous from within. One major function of gap junctions is to ensure a supply of nutrients to cells of an organ that are not in direct contact with the blood supply. Gap junctions are formed from a type of protein called a connexin.

Given the predominant lipid nature of biological membranes many types of molecules are restricted in their ability to diffuse across a membrane. This is especially true for charged ions, water and hydrophilic compounds. The barrier to membrane translocation is overcome by the presence of specialized channels and transporters. Although channels and transporters are required to move many types of molecules and compounds across membranes, some substances can pass through from one side of a membrane to the other through a process of diffusion. Diffusion of gases such as O₂, CO₂, NO, and CO occurs at a rate that is solely dependent upon concentration gradients. Lipophilic molecules will also diffuse across membranes at a rate that is directly proportional to the solubility of the compound in the membrane. Although water can diffuse across biological membranes, the physiological need for rapid equilibrium across plasma membranes has lead to the evolution of a family of water transporting channels that are called aquaporins.

 

Membrane channels

The definition of a channel (or a pore) is that of a protein structure that facilitates the translocation of molecules or ions across the membrane through the creation of a central aqueous channel in the protein. This central channel facilitates diffusion in both directions dependent upon the direction of the concentration gradient. Channel proteins do not bind or sequester the molecule or ion that is moving through the channel. Specificity of channels for ions or molecules is a function of the size and charge of the substance. The flow of molecules through a channel can be regulated by various mechanisms that result in opening or closing of the passageway.

Membrane channels are of three distinct types. The α-type channels are homo- or hetero-oligomeric structures that in the latter case consist of several dissimilar proteins. This class of channel protein has between 2 and 22 transmembrane α-helical domains which explains the derivation of their class. Molecules move through α-type channels down their concentration gradients and thus require no input of metabolic energy. Some channels of this class are highly specific with respect to the molecule translocated across the membrane while others are not. In addition, there may be differences from tissue to tissue in the channel used to transport the same molecule. As an example, there are over 15 different K⁺-specific voltage-regulated channels in humans. The transport of molecules through α-type channels occurs by several different mechanisms. These mechanisms include changes in membrane potential (termed voltage-regulated or voltage-gated), phosphorylation of the channel protein, intracellular Ca²⁺, G-proteins, and organic modulators.

The β-barrel channels (also called porins) are so named because they have a transmembrane domain that consists of β-strands forming a β-barrel structure. Porins are found in the outer membranes of mitochondria. The mitochondrial porins are voltage-gated anion channels that are involved in mitochondrial homeostasis and apoptosis.

The pore-forming toxins represent the third class of membrane channels. Although this is a large class of proteins first identified in bacteria, there are a few proteins of this class expressed in mammalian cells. The defensins are a family of small cysteine-rich antibiotic proteins that are pore-forming channels found in epithelial and hematopoietic cells. The defensins are involved in host defense against microbes (hence the derivation of their name) and may be involved in endocrine regulation during infection.

 

Membrane transporters

Transporters are distinguished from channels because they catalyze (mediate) the movement of ions and molecules by physically binding to and moving the substance across the membrane. Transporter activity can be measured by the same kinetic parameters applied to the study of enzyme kinetics. Transporters exhibit specificity for the molecule being transported as well as show defined kinetics in the transport process. Transporters can also be affected by both competitive and noncompetitive inhibitors. Transporters are also known as carriers, permeases, translocators, translocases, and porters. The action of transporters is divided into two classifications: passive-mediated transport (also called facilitated diffusion) and active transport. Facilitated diffusion involves the transport of specific molecules from an area of high concentration to one of low concentration which results in an equilibration of the concentration gradient. Glucose transporters are a good example of passive-mediated (facilitative diffusion) transporters. Another important class of passive-mediated transporters are the K⁺ channels.

In contrast, active transporters transport specific molecules from an area of low concentration to that of high concentration. Because this process is thermodynamically unfavorable, the process must be coupled an exergonic process, e.g. hydrolysis of ATP. There are many different classes of transporters that couple the hydrolysis of ATP to the transport of specific molecules. In general these transporters are referred to as ATPases. These ATPases are so named because they are autophosphorylated by ATP during the transport process. There are four different types of ATPases that function in eukaryotes: E-type ATPases are cell surface transporters that hydrolyze a range of nucleoside triphosphates that includes extracellular ATP; F-type ATPases function in the translocation of H⁺ in the mitochondria during the process of oxidative phosphorylation; F-type transporters contain rotary motors; P-type ATPases are mostly found in the plasma membrane and are involved in the transport of H⁺, K⁺, Na⁺, Ca²⁺, Cd²⁺, Cu²⁺, and Mg²⁺. These transporters represent one of the largest families found in both prokaryotes and eukaryotes; V-type ATPases are located in acidic vesicles and lysosomes and have homology to the F-type ATPases and also contain rotary motors like F-type ATPases. A-type ATPases are archaeal bacterial transporters that function like the F-type class of ATPases.

 

The ABC family of transporters

The ABC transporters comprise the ATP-binding cassette transporter superfamily. All members of this superfamily of membrane proteins contain a conserved ATP-binding domain and use the energy of ATP hydrolysis to drive the transport of various molecules across all cell membranes. There are 48 known members of the ABC transporter superfamily and they are divided into seven subfamilies based upon phylogenetic analyses. These seven subfamilies are designated ABCA through ABCG. Each member of a given subfamily is distinguished with numbers (e.g. ABCA1). In order to keep the size of the following Table limited, only those ABC transporters (of the 48 known genes) whose functions have been defined or assessed by in vitro assays are included.

Gene Symbol	Other Names	Chromosome	Functions/Comments
ABCA1	ABC1	9q31.1	transfer of cellular cholesterol and phospholipids to HDLs (reverse cholesterol transport), defects in gene associated with development of Tangier disease
ABCA2	ABC2	9q34	role in delivery of LDL-derived free cholesterol to the endoplasmic reticulum for esterification, involved in protection against reactive oxygen species, drug resistance
ABCA4	ABCR	1p22.1–p22	expressed exclusively in retinal photoreceptors, efflux of all trans-retinal aldehyde
ABCB1	PGY1, MDR1	7p21.1	PGY1=P-glycoprotein 1; MDR1=multidrug resistance protein 1, multidrug resistance P-glycoprotein, is an integral component of the blood-brain barrier, transports a number of drugs from the brain back into the blood
ABCB2	TAP1, PSF1, APT1	6p21.3	TAP1=transporter, ATP-binding cassette, major histocompatibility complex (MHC), 1; PSF1=peptide supply factor 1; APT1=antigen peptide transporter1; peptide transport from cytosol to MHC class I molecules in the ER; functions as a heterodimer with ABCB3/TAP2
ABCB3	TAP2, PSF2, APT2	6p21	TAP2=transporter, ATP-binding cassette, major histocompatibility complex (MHC), 2; PSF2=peptide supply factor 2; APT2=antigen peptide transporter1; peptide transport from cytosol to MHC class I molecules in the ER; functions as a heterodimer with ABCB2/TAP1
ABCB4	PGY3, MDR3	77q21.1	PGY3=P-glycoprotein 3; MDR3=multidrug resistance protein 3, class III multidrug resistance P-glycoprotein, canalicular phospholipid translocator, biliary phosphatidylcholine transport, defects in gene associated with 6 liver diseases: progressive familial intrahepatic cholestasis type 3 (PFIC3), adult biliary cirrhosis, transient neonatal cholestasis, drug-induced cholestasis, intrahepatic cholestasis of pregnancy, and low phospholipid-associated cholelithiasis syndrome
ABCB6	MTABC3	1q42	mitochondrial transporter involved in heme biosynthesis, transports porphyrins into mitochondria
ABCB7	ABC7	Xq12–q13	iron-sulfur (Fe/S) cluster transport
ABCB11	BSEP, SPGP	2q24	BSEP=bile salt export protein, bile salt transport out of hepatocytes, gene defects associated with progressive familial intrahepatic cholestasis type 2 (PFIC2)
ABCC1	MRP1	16p13.1	MRP1=multidrug resistance associated protein 1, sphingosine-1-phosphate (S1P) release from mast cells which enhances their migration, uses glutathione as a co-factor in mediating resistance to heavy metal oxyanions
ABCC2	MRP2, CMOAT	10q24	MRP2=multidrug resistance associated protein 2, CMOAT=canalicular multispecific organic anion transporter, biliary excretion of many non-bile organic anions, gene defects result in Dubin-Johnson syndrome
ABCC3	MRP3, CMOAT3	17q21.3	MRP3=multidrug resistance associated protein 3, CMOAT3=canalicular multispecific organic anion transporter, drug resistance
ABCC4	MRP4, MOATB	13q32	MRP4=multidrug resistance associated protein 4, MOATB=multispecific organic anion transporter B, enriched in prostate, regulator of intracellular cyclic nucleotide levels, mediator of cAMP-dependent signal transduction to the nucleus
ABCC5	MRP5, MOATC	3q27	MRP5=multidrug resistance associated protein 5, MOATB=multispecific organic anion transporter C, resistance to thiopurines and antiretroviral nucleoside analogs
ABCC6	MRP6, PXE	16p13.1	MRP6=multidrug resistance associated protein 6, PXE=pseudoxanthoma elasticum, a rare disorder in which the skin, eyes, heart, and other soft tissues become calcified
CFTR	ABCC7	7q31.2	CFTR=cystic fibrosis transmembrane conductance regulator, chloride ion channel, gene defects result in cyctic fibrosis
ABCC8	SUR	11p15.1	SUR=sulfonylurea receptor, target of the type 2 diabetes drugs such as glipizide
ABCD1	ALD	Xq28	involved in the import and/or anchoring of very long-chain fatty acid-CoA synthetase (VLCFA-CoA synthetase) to the peroxisomes, gene defects result in X-linked adrenoleukodystrophy (XALD)
ABCD2	ALDR	12q12	adrenoleukodystrophy-related protein, also found in peroxisomal membranes, modifier that contributes to phenotypic variability seen in XALD, can restore peroxisomal fatty acid oxidation defect of XALD liver cells
ABCD3	PMP70, PXMP1	1p21.3	70kDa peroxisomal membrane protein, also called peroxisomal membrane protein 1, mutation associated with Zellweger syndrome 2 (ZWS2)
ABCD4	PMP69, P70R, PXMP1L	14q24.3	related to the other ABCD family members but localized to ER membranes, also called peroxisomal membrane protein 1-like, mutations increase severity of XALD
ABCE1	OABP, RNS4I	4q31	OABP=oligoadenylate binding protein; RNS4I=Ribonuclease 4 inhibitor
ABCG1	ABC8, White1	21q22.3	involved in mobilization and efflux of intracellular cholesterol, responsible for approximately 20% of cholesterol efflux to HDLs (reverse cholesterol transport)
ABCG2	ABCP, MXR, BCRP	4q22	ABCP=ATP-binding cassette transporter, placenta-specific; MXR=mitoxantrone-resistance protein; BCRP=breast cancer resistance protein, xenobiotic transporter, plays a major role in multidrug resistance, heme and porphyrin export
ABCG4	White2	11q23.3	expression restricted to astrocytes and neurons, cholesterol and sterol efflux to HDL-like particles in the CNS, may function in sterol transport with ABCG1 in cells where the two genes are co-expressed, may increase lipidation of apoE in Alzheimer disease
ABCG5	White3	2p21	forms an obligate heterodimer with ABCG8, expressed in intestinal enterocytes and hepatocytes, functions to limit plant sterol and cholesterol absorption from the diet by facilitating efflux out of enterocytes into the intestinal lumen and out of hepatocytes into the bile
ABCG8	Sterolin 2	2p21	see above for ABCG5

 

The solute carrier family of transporters

The solute carrier (SLC) family of transporters includes over 300 proteins functionally grouped into 47 families. The SLC family of transporters includes facilitative transporters, primary and secondary active transporters, ion channels, and the aquaporins. The aquaporins are so named because they constitute water channels (see above). Given the scope of this discussion it is not possible to cover all of the transporters in each of the 47 families. Listed below are several of the families of SLC transporters and within each family is a description of several member proteins. All of the members of a particular family are not included due to space limitations. Focus is primarily on solute carriers discussed on other web pages in this site or due to known clinical significance.

SLC Family	Functional Class	Member Names / Comments
1	high affinity glutamate and neutral amino acid transporters	SLC1A1, SLC1A2, SLC1A3, SLC1A4, SLC1A5, SLC1A6, SLC1A7 SLC1A4 and SLC1A5 are the neutral amino acid transporters decreased expression of SLC1A2 is associated with amyotrophic lateral sclerosis (ALS = Lou Gehrig disease)
2	facilitative GLUT transporters	SLC2A1, SLC2A2, SLC2A3, SLC2A4, SLC2A5, SLC2A6, SLC2A7, SLC2A8, SLC2A9, SLC2A10, SLC2A11, SLC2A12, SLC2A13, SLC2A14 SLC2A1 is GLUT1. This glucose transporter is ubiquitously expressed in various tissues but only at low levels in liver and skeletal muscle. This is the primary glucose transporter in erythrocytes. SCL2A2 is GLUT2. This glucose transporter is expressed predominantly in the liver, pancreatic β-cells, kidney, and intestines. SCL2A3 is GLUT3. This glucose transporter is found primarily in neurons and possess the lowest Km for glucose of any of the glucose transporters. SLC2A4 is GLUT4. This glucose transporter is expressed predominantly in insulin-responsive tissues such as skeletal muscle and adipose tissue. SLC2A5 is GLUT5 which is now known to be involved in fructose transport not glucose transport. SCL2A13 is also called the proton (H+) myo–inositol cotransporter, HMIT SLC2A9 (GLUT9) is a major uric acid transporter in the liver and kidneys
3	heavy subunits of heteromeric amino acid transport	SLC3A1, SLC3A2
4	bicarbonate transporters	SLC4A1, SLC4A2, SLC4A3, SLC4A4, SLC4A5, SLC4A7, SLC4A8, SLC4A9, SLC4A10, SLC4A11 SLC4A7 was formerly identified as SLC4A6 and so the SLC4A6 identity is no longer used
5	sodium glucose co–transporters	SLC5A1, SLC5A2, SLC5A3, SLC5A4, SLC5A5, SLC5A6, SLC5A7, SLC5A8, SLC5A9, SLC5A10, SLC5A11, SLC5A12 SLC5A2 is also known as SGLT2 which is responsible for the majority of glucose re-absorption by the kidneys and as such is a current target of therapeutic intervention in the hyperglycemia associated with type 2 diabetes
6	sodium– and chloride–dependent neurotransmitter transporters	SLC6A1, SLC6A2, SLC6A3, SLC6A4, SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC6A10, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A20 SLC6A19 is involved in neutral amino acid transport, deficiency results in Hartnup disorder; protein also called system B0 neutral amino acid transporter 1 (B0AT1)
7	cationic amino acid transporters and the glycoprotein-associated amino acid transporters	SLC7A1, SLC7A2, SLC7A3, SLC7A4, SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A9, SLC7A10, SLC7A11
8	Na+/Ca2+ exchangers (NCK proteins)	SLC8A1, SLC8A2, SLC8A3
9	Na+/H+ exchangers	SLC9A1, SLC9A2, SLC9A3, SLC9A4, SLC9A5, SLC9A6, SLC9A7, SLC9A8, SLC9A9, SLC9A10
10	sodium bile salt cotransporters	SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5, SLC10A7 SLC10A1: also called NTCP for Na+-taurocholate cotransporting polypeptide, NTCP is involved in hepatic uptake of bile acids through the sinusoidal/basolateral membrane SLC10A3, SLC10A4, and SLC10A5 are considered orphan transporters
11	proton-coupled metal ion transporters	SLC11A1, SLC11A2, SLC11A3 SLC11A2 is also known as the divalent metal-ion transporter-1 (DMT1) SLC11A3 is now referred to as SLC40A1, this protein is more commonly called ferroportin, but is also known as iron-regulated gene 1 (IREG1), and reticuloendothelial iron transporter (MPT1)
12	electroneutral cation/Cl– cotransporter	SLC12A1, SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A6, SLC12A7, SLC12A8, SLC12A9
13	Na+–sulfate/carboxylate cotransporters	SLC13A1, SLC13A2, SLC13A3, SLC13A4, SLC13A5
14	urea transporters	SLC14A1, SLC14A2
15	proton oligopeptide cotransporters	SLC15A1, SLC15A2, SLC15A3, SLC15A4
16	monocarboxylate transporters	SLC16A1, SLC16A2, SLC16A3, SLC16A4, SLC16A5, SLC16A6, SLC16A7, SLC16A8, SLC16A9, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14
17	organic anion transporters; originally identified as type I Na+–phosphate cotransporters	SLC17A1, SLC17A2, SLC17A3, SLC17A4, SLC17A5, SLC17A6, SLC17A7, SLC17A8, SLC17A9
18	vesicular amine transporters	SLC18A1, SLC18A2, SLC18A3
19	folate/thiamine transporters	SLC19A1, SLC19A2, SLC19A3
20	type III Na+–phosphate cotransporters	SLC20A1, SLC20A2 also called Pit-1 and Pit-2 (Pi=inorganic phosphate, t=transporter)
21 SLCO	organic anion transporting polypeptides (OATP)	there are at least 11 human SLCO family members divided into 6 subfamilies identified as 1 through 6 these transporters have the nomenclature SLCO followed by the family number, subfamily letter, and member number; e.g. SLCO1B1 is a sinusoidal/basolateral membrane Na+-independent transporter, also called the organic anion transporting polypeptide 1B1 (OATP1B1). SLCO1B1 was formerly identified as OATPC and also as SLC21A6.
22	organic cation transporters (OCTs), zwitterion/cation transporters (OCTNs) and  organic anion transporters (OATs)	SLC22A1, SLC22A2, SLC22A3, SLC22A4, SLC22A5, SLC22A6, SLC22A7, SLC22A8, SLC22A9, SLC22A10, SLC22A11, SLC22A12, SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A20 SLC22A18: found in the imprinted region of chromosome 11 associated with Beckwith-Wiedemann syndrome (BWS)
23	Na+–dependent ascorbic acid transporters	SLC23A1, SLC23A2, SLC23A3, SLC23A4 also identified as SVCT1, SVCT2, SVCT3, and SVCT4 SLC23A3 and SLC23A4 are orphan transporters
24	Na+/Ca2+–K+ exchangers (NCKX proteins)	SLC24A1, SLC24A2, SLC24A3, SLC24A4, SLC24A5, SLC24A6
25	mitochondrial carriers	SLC25A1, SLC25A2, SLC25A3, SLC25A4, SLC25A5, SLC25A6, SLC25A7, SLC25A8, SLC25A9, SLC25A10, SLC25A11, SLC25A12, SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A18, SLC25A19, SLC25A20, SLC25A21, SLC25A22, SLC25A27
26	multifunctional anion exchangers	SLC26A1, SLC26A2, SLC26A3, SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A8, SLC26A9, SLC26A11 SLC26A10 is a pseudogene
27	fatty acid transporters (FATPs)	SLC27A1, SLC27A2, SLC27A3, SLC27A4, SLC27A5, SLC27A6 FATP2 is also known as very long-chain acyl-CoA synthetase (VLCS); FATP5 is also known as very long-chain acyl-CoA synthetase-related protein (VLACSR) or very long-chain acyl-CoA synthetase homolog 2 (VLCSH2); FATP6 is also known as very long-chain acyl-CoA synthetase homolog 1 (VLCSH1)
28	Na+–dependent concentrative nucleoside transport (CNTs)	SLC28A1, SLC28A2, SLC28A3
29	equilibrative nucleoside transporters (ENTs)	SLC29A1, SLC29A2, SLC29A3, SLC29A4
30	efflux and compartmentalization of zinc (ZNTs)	SLC30A1, SLC30A2, SLC30A3, SLC30A4, SLC30A5, SLC30A6, SLC30A7, SLC30A8, SLC30A9, SLC30A10 polymorphisms in the gene encoding SLC30A8 are associated with increased diabetes risk
31	copper transporters (CTRs)	SLC31A1, SLC31A2 these mediate copper uptake ATP7A and ATP7B are related copper transporting ATPases that mediate copper export ATP7A is defective in Menkes disease and ATP7B is defective in Wilson disease
32	vesicular inhibitory amino acid transporter (VIAAT)	SLC32A1 also called vesicular GABA transporter (VGAT)
33	acetyl-CoA transporter (ACATN)	SLC33A1
34	type II Na+–phosphate cotransporters	SLC34A1, SLC34A2, SLC34A3
35	nucleoside sugar transporters	at least 17 family members in humans divided into five subfamilies identified as A through E SLC35C1 is also identified as the GDP-fucose transporter (gene symbol = FUCT1)
36	proton–coupled amino acid transporters	SLC36A1, SLC36A2, SLC36A3, SLC36A4
37	sugar–phosphate/phosphate exchangers (SPXs)	SLC37A1, SLC37A2, SLC37A3, SLC37A4 SLC37A4 is also known as glucose-6-phosphate transporter-1 (G6PT1) which is defective in glycogen storage disease type1b
38	sodium–coupled neutral amino acid (system N/A) transporters (SNATs)	System A family includes SLC38A1, SLC38A2, SLC38A4 System N family includes SLC38A3, SLC38A5, SLC38A6
39	metal ion transporters (ZIPs)	SLC39A1, SLC39A2, SLC39A3, SLC39A4, SLC39A5, SLC39A6, SLC39A7, SLC39A8, SLC39A9, SLC39A10, SLC39A11, SLC39A12, SLC39A13, SLC39A14
40	basolateral iron transporter	SLC40A1 is more commonly known as as ferroportin, but is also known as iron-regulated gene 1 (IREG1) or reticuloendothelial iron transporter (MTP1); was also identified as SLC11A3 which is no longer used
41	MgtE–like magnesium transporters	SLC41A1, SLC41A2, SLC41A3 MgtE is a divalent cation transporter first identified in the bacteria Chlamydomonas reinhardtii
42	Rh ammonium transporters	SLC42A1, SLC42A2, SLC42A3 also identified as RhAG, RhBG, RhCG these transporters are named for the Rh blood–group antigens; e.g. RhAG is encoded by the RHAG gene which is also designated as the CD241 gene (cluster of differentiation 241)
43	Na+–independent, system–L like amino acid transporters	SLC43A1, SLC43A2, SLC43A3
44	chlorine–like transporters	SLC44A1, SLC44A2, SLC44A3, SLC44A4, SLC44A5
45	putative sugar transporters	SLC45A1, SLC45A2, SLC54A3, SLC45A4
46	heme transporters	SLC46A1, SLC46A2
47	multidrug and toxin extrusion	SLC47A1, SLC47A2

 

Clinical significances of transporter defects

As might be expected, defects in the expression and/or function of membrane transporters leads to the manifestation of numerous clinical disorders, including defects in ABCB7 (a protein localized to the inner mitochondrial membrane and involved in iron homeostasis) are associated with X-linked sideroblastic anemia with ataxia (XSAT) which is characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis; defects in many members of the SLC6 family are associated with mental retardation, affective disorders, and other neurological dysfunctions (SLC6A1 defects are associated with epilepsy and schizophrenia; SLC6A2 defects are associated with depression and anorexia nervosa; SLC6A3 defects are associated with Parkinsonism, Tourette syndrome, ADHD, and substance abuse; SLC6A4 defects are associated with anxiety disorder, depression , autism, and substance abuse);