40: Membrane Transporters

diffusion:

movement of substance from high concentration area to low concentration area

• doesn’t require energy

• fastest for charge-neutral compounds

• facilitated diffusion requires protein

active transport:

• requires proteins and energy

• moves molecule from low to high concentration area

facilitated diffusion:

• moves molecule from high to low concentration area

• requires proteins but not energy

H+/K+ pump:

found in lining of stomach within gastric parietal cells

• releases H+ into stomach and takes back K+ into cell

• builds stomach acid

galactoside permease:

• secondary active transport for lactose

• uses energy for transport from H+ gradient

ABC transporters:

• primarily dimers

• transmembrane domain has alpha helices (12) embedded in bilayer

• binds ATP and a substrate

• removes drugs from cell → lowers intracellular drug concentration

• activity can lead to drug resistance

Mechanism of ABC transporters:

substrate binds to intracellular side of transmembrane protein → ATP bind changes conformation of protein → substrate is secreted into extracellular space → ATP hydrolysis → ADP release restore protein to open dimer conformation

P-glycoprotein (ABCB1):

• expressed in intestinal epithelium, hepatocytes, renal proximal tubular cells, BBB

• ATP-dependent

• binding of drug leads to increased transcription of this gene

Why do cancer cells express high levels of p-glycoprotein?

P-gp effluxes anti-cancer drugs out of cancer cells so once pt’s tumor is resistant to one type of therapy, it’s likely resistant to other therapies as well

solute carrier transporters (SLC):

• doesn’t require ATP

• can be either facilitative or secondary active transporters

• can either uptake or efflux

What are substrates of SLCs?

• inorganic ions

• nucleotides

• amino acids

• neurotransmitters

• sugars/purines/fatty acids

• drugs

Which SLC transporters are drug targets?

• glucose: for diabetes

• neurotransmitter: for antidepressants

• bile acid: for bile acid related disease

• salt: for diuretics

• uric acid reabsorption: for gout

• peptide: for better drug delivery

What does SLC5A1 encode?

SGLT1 which has a major role in glucose absorption in the small intestine

What does SLC5A2 encode?

SGLT2 which plays a major role in renal glucose reabsorption

SLC5 transporters:

targets for diabetes drugs (-flozin) that have notable effects on reducing blood sugar levels and increasing urinary glucose excretion

What does SLC6A2 encode?

norepinephrine transporter (NET), which is the reuptake transporter of norepinephrine into presynaptic neurons

What does SLC6A4 encode?

serotonin transporter (SERT), which is the reuptake transporter of serotonin into presynaptic neurons

SLC6 transporters:

targets for antidepressants like SSRIs and SNRIs, which reduce clearance of serotonin from synapse by increasing activation of neurotransmitters on ligand-gated ion channels and GPCR signaling

What does SLC10A2 encode?

apical Na-dependent bile acid transporter (ASBT), which plays a key role in the enterohepatic circulation of bile acids

What does SLC12A1 encode?

Na+-K+-Cl- cotransporter 2 (NKCC2), which is the major salt transporter in the kidney that maintains urinary concentration + blood pressure

What does SLC22A12 encode?

urate transporter 1 (URAT1), the primary uric acid reabsorption transporters expressed in the kidney

What does SLC15A1 and SLC15A2 encode?

peptide transporter 1 (PepT1) and PepT2 which are the major route of dietary di/tripeptide absorption in the small intestine and kidneys

A decrease in transporter expression in a clearance organ can lead to:

increased drug concentrations in plasma and target organs