Transporters II

Question 1

What does ABC stand for?

Answer 1

ATP-Binding Cassette

Question 2

What are ABC transporters made of?

Answer 2

multiple subunits that include transmembrane proteins and membrane-associated ATPases

Question 3

What do all ATPase subunits need to translocate substrates across membranes?

Answer 3

Energy from hydrolysis in of ATP

Question 4

ABC transporters are considered to be an ABC superfamily based on _______?

Answer 4

molecular homology of the sequence and organization of their ABC domains

Question 5

What is the role of ABC uptake transporters?

Answer 5

Shuttle a variety of nutrients for cell health

Question 6

What is the role of ABC efflux transporters?

Answer 6

Shuttle lipids, sterols, drugs, etc primarily as a detoxication mechanism

Question 7

How many ABC genes are there (currently) in humans?

Answer 7

48 ABC genes

Question 8

How were ABC transporters first identified?

Answer 8

Due to their roles in their drug resistance

Question 9

What are the four core proteins of the ABC transporters?

Answer 9

Two trans-membrane subunits (alternate between inwards and outwards facing orientation and two cytosolic subunits

Question 10

Why does the structure of the transmembrane domains matter?

Answer 10

Because the structure dictates specificity (what the transporters will transport)

Question 11

What causes the conformational change in the nucleotide and what does it do?

Answer 11

Binding of substrate to the transmembrane domains; allows 2 ATP molecules to bind

Question 12

What is the Vacuum cleaner mechanism?

Answer 12

Closing of outer “open” conformation → Substrate gets fully internalized to the transport pore → Opening of the inner side of the transporter → Substrate gets sucked into the cell

Question 13

What are the three most studied and relevant ABC exporters in pharmacology?

Answer 13

P-glycoprotein (P-gp/ABCB1), Multidrug resistance-associated protein 1 (MRP1/ABCC1), and Breast cancer resistance protein (BCRP/ABCG2)

Question 14

What are the four main nomenclatures in the ABC transporter family and what is their function?

Answer 14

ABCA, ABCB, ABCC, ABCG; transports drugs

Question 15

What does OATPs stand for?

Answer 15

Organic Anion Transporters

Question 16

What are OATPs?

Answer 16

Na⁺-independent facilitated transporters that facilitate the flux of large amphipathic organic anions and neutral/cationic drugs

Question 17

What are some examples of large amphipathic organic anions and neutral/cationic drugs?

Answer 17

Statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensive, and anti-cancer drugs

Question 18

How many recognizable subfamilies do mammalian OATPs have?

Answer 18

Five recognizable subfamilies

Question 19

What are the proteins relevant to pharmacology?

Answer 19

OATP2B1 (statins, ACE inhibitors, Angiotensin Receptor blockers, antibiotics, antihistamines, antihypertensives, and anticancer drugs) and OATP1B1 and OATP1B3 (anti-cancer drugs of the kinase inhibitor family)

Question 20

What is the mechanism of transport for OATPs?

Answer 20

Facilitated transporters that do not use ATP

Question 21

What are the two general mechanisms for OATPs?

Answer 21

Countercurrent exchange of one anion in, with another anion out, Countercurrent exchange of two anions - two in, two out

Question 22

What are Organic Cation Transporters (OCTs)?

Answer 22

Members of the solute carrier (SLC) superfamily that work to eliminate endogenous small organic cations as well as many drugs in the liver, kidney, and intestine

Question 23

What are mutations/deficiencies of OCTs associated with?

Answer 23

Diseases such as gout (hyperuricemia), carnitine (important amino acid) deficiency, Wilms tumors, adrenocortical carcinoma, and lung, ovarian, and breast cancer

Question 24

What is the role of OCT1 (SLC22A1)?

Answer 24

Disposition and hepatic clearance of mostly cationic drugs and endogenous compounds. It works with MATE1 (in the liver sinusoids; blood side) to facilitate biliary elimination of OCT1 substrates direct to the intestine. It is required for the uptake of the drug metformin in cells

Question 25

Where can you find OCT1 (SLC22A1)?

Answer 25

Liver and brain

Question 26

What is the role of OCT1 (SLC22A1)?

Answer 26

Functions together with other transporters called MATE1 and MATE2-K in the kidney to eliminate OCT2 substrates into the urine. The important drug substrates under this include metformin (antidiabetic), cisplatin and oxaliplatin (chemotherapy) lamivudine (anti-HIV)

Question 27

Where can you find OCT2 (SLC22A2)?

Answer 27

Human kidney tubules

Question 28

What happens with the natural transport activity in OCT3 (SLC22A3)?

Answer 28

Psychoactive drugs (Molly, E, PCP, amphetamine, methamphetamine and cocaine) inhibit the transport of serotonin and dopamine

Question 29

What happens when psychoactive drugs inhibit the homeostasis of histamine, serotonin, and dopamine?

Answer 29

Upsets the brain chemistry in the mood/reward centers, and so leading to addiction (person has to take in more and more of the drug so that they feel "happy")

Question 30

What causes the drug-drug interactions for OCT3 for kidney elimination?

Answer 30

Alters pharmacokinetics

Question 31

Explain what happens in the drug-drug interaction in OCT3

Answer 31

Drugs compete for the kidney, and cimetidine (anti-ulcer drug) "wins" and inhibits the clearance of the other drugs. This causes higher levels of drugs in the same dose as well as drug-drug interaction. Higher level of drugs in the systems could be fatal as it can cause adverse drug reactions

Question 32

What are the two mechanisms of OTPs?

Answer 32

ATP independent and Facilitated diffusion, countercurrent exchange (ion gradient is the driving force)

Question 33

What is the influx mechanism for OTPs?

Answer 33

Electrogenic facilitated diffusion, which is the nonspecific flux of cationic solutes. This mechanism is opportunistic, meaning it is not a continuous catalytic cycle (mechanism in kidney tubules)

Question 34

What is the efflux mechanism in OTPs?

Answer 34

Counter exchange of substrate for H+ ions (mechanism in the kidney)

Question 35

What is the importance of the influx and efflux mechanisms?

Answer 35

Keeps balance of the electrolytes in the body