4. Active transport processes. ABC proteins, SLC proteins Flashcards
active transport
They transport ions against their electrochemical potential gradients or uncharged molecules against their concentration gradients using the energy directly from ATP hydrolysis (e.g. Na+/K+-pump, Ca2+-pump, P-glycoprotein, V-types proton ATPase of lysosomes), or indirectly by ion flow provided by an existing ion gradient (co-transport, secondary active transport).
secondary active transporters
In contrast with primary active transport, there is no direct coupling to ATP hydrolysis; instead, the electrochemical potential difference of an ion is used. E.g. glucose-Na symport, amino-acid- Na symport: these symporters take up glucose and amino acids from the lumen of small intestine into the intestinal epithelia on the expense of sodium uptake into the epithelial cells. The sodium electrochemical gradient is maintained by the Na+/K+ ATPase at the expense of ATP hydrolysis.
Na/glucose coupled transport
A secondary active transport. The Na/glucose symporter transports 2 Na+ and one glucose molecules into the cells simultaneously and in the same direction, at the apical surface of epithelial cells of small intestine (facing intestinal lumen). The electrochemical potential of Na+ covers energetically the transport of glucose against its concentration gradient. The Na+/K+-ATPase pump in the membrane maintains the Na+ electrochemical gradient required for this process.
V-type transporters
Vacuolar-type proton transporters in the membrane of membrane enclosed organelles which transport protons into these organelles. E.g. they are responsible for the low pH of lysosomes. During ATP hydrolysis, the transporter does not become covalently phosphorylated (transiently), in contrast with P-type transporters.
P-type transporters (with 2 examples)
During their operation, they are phosphorylated transiently and the conformation change elicited by this leads to the transport of the ion transported by the given transporter. The Na+/K+ -ATPase or plasma membrane Ca2+-ATPase create ion gradients required for essential operations of cells and are present in all types of cells.
ABC proteins
They consist of two ATP-binding sites (NBDs) responsible for binding and hydrolysis of ATP molecules and two transmembrane domains (TMDs) that collectively form the substrate binding sites. The structure of the NBDs as well as the mechanism of ATP hydrolysis is shared among all ABC proteins. Based on their function ABC proteins are categorized into channel- type proteins (e.g. CFTR), channel regulators (e.g. SUR1) and active pumps (e.g. Pgp=ABCB1, ABCG2, TAP1/TAP1).
Cystic fibrosis transmembrane conductance regulator = CFTR=ABCC7
It is a channel type ABC protein. This is a chloride channel expressed in the apical membrane of epithelial cells. Channel openig is induced by ATP binding of the nucleotide binding domain (NBD) and the phosporylation of the regulatory (R) domain by protein kinase A.Through open CFTR channels Cl- exits from the epithelial cell to the covering mucus. Na+ ions follow passively, increasing osmotic pressure outside and resulting in the movement of water out of the cell.
Inactivating mutations of the CFTR Cl–ion channel cause cystic fibrosis (CF), which is a multiorgan hereditary disease. The high viscosity of secreted mucus casuse symptoms affecting the lungs, the gastro-intestinal system and the reproductive system as well. Patients often die because of serious recurrent lung infections casued by the retention of the thick mucus in the lungs.
multidrug resistance
Resistance of cancer cells to numerous structurally or functionally unrelated anticancer agents, which are extruded from the cells by ABC transporters and consequently cannot reach lethal intracellular concentration. This phenomenon is caused by the expression of certain ABC transporters in the plasma membrane of tumor cells including P-glycoprotein, ABCG2 and multidrug resistance protein (ABCC1, MRP2).
TAP1/TAP2 oligopeptide transporter
It is a heterodimeric transporter formed by half transporter molecules TAP1 and TAP2. The TAP1/TAP2 transporter is expressed in the endoplasmic reticulum (ER) membrane. It pumps oligopeptides formed upon the proteasomal degradation of cellular and certain viral proteins into the lumen of the ER, where they bind to the MHC I protein and the complex is transported to the plasma membrane to be presented to cytotoxic T-cells. Inactivating mutations of TAP1/TAP2 may lead to immunodeficiency.
ABCG2 (Breast Cancer Resistance Protein, BCRP)
It is an active transporter type ABC protein with a wide substrate spectrum partially overlapping with the substrate spectrum of Pgp involving xenobiotics and numerous structurally unrelated anticancer agents. Besides tumor cells it is expressed in barrier regions of the body and in stem cells. Its physiological substrate is uric acid, and is thus also involved in the elimination of uric acid from the body. Mutations affecting the function of ABCG2 increase the risk of gout.
sulfonylurea receptor 1 (SUR1), KATP channel
SUR1 (ABCC8) is a channel regulator type ABC protein. Together with the pore forming Kir6.2 subunits SUR1 molecules form an ATP-sensitive KATP potassium channel localized in the plasma membrane of pancreatic β cells. It is involved in the regulation of insulin secretion. An increased ATP/ADP ratio caused by elevated blood glucose results in the in closure of the KATP channels, which depolarizes the β-cell and leads to the opening of voltage-gated Ca2+ channels in the plasma membrane. The concomitant increase in Ca2+ entry and rise in the cytosolic free Ca2+ concentration causes the release of insulin stored in vesicles.
