Membrane Transport and Proteins

Membrane Transport

• Smaller, nonpolar molecules diffuse more rapidly across lipid bilayers.
• Examples of molecules that diffuse rapidly across lipid bilayers are O2 and CO2.
• Small, uncharged polar molecules like water or urea diffuse across bilayers more slowly.
• Lipid bilayers are highly impermeable to charged molecules (ions), regardless of size.

Passive Transport

• Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes.

Active Transport

• Active transport requires energy to move substances across cell membranes

Classes of Membrane Proteins

• Carrier proteins/transporters bind and transfer specific solutes across the lipid bilayer
• This involves conformational changes that sequentially expose the solute-binding site on either side of the membrane.
• Channel proteins form a pore through the membrane to enable passage of solutes

Uniporters

• Uniporters transport only one solute at a time.
• Facilitated diffusion by uniporters is much faster than passive diffusion.
• Transport is limited by the number of uniporter molecules, not the entire phospholipid bilayer

Glucose Transporters (GLUTs)

• GLUTs are membrane proteins facilitating glucose transport across the plasma membrane.
• GLUT1 uniporters transport glucose into most mammalian cells.
• Insulin stimulates glucose uptake by relocating GLUT4 transporters to the membrane in adipose and muscle tissues.

Symport

• Symporters transport two or more solutes simultaneously in the same direction (cotransport).

Antiport

• Antiporters transport two or more solutes in opposite directions (countertransport).
• The sodium-potassium pump uses antiport, bringing K+ into the cell and removing Na+

Sodium-Potassium Pump

• Crucial for maintaining resting potential and regulating cell volume in animal cells
• A significant consumer of ATP in animal cells

ATP-Driven Pumps

• P-class pumps: Found in plasma membranes of plants, fungi, bacteria (H+ pump) and higher eukaryotes (Na+/K+ pump), the apical plasma membrane of mammalian stomach (H+/K+ pump), plasma membranes of all eukaryotic cells(Ca2+ pump).
• V-class proton pumps: Vacuolar membranes in plants, yeast and fungi, endosomal, lysomal, and inner mitochrondrial mambranes in animal cells.
• F-class proton pumps: Bacterial plasma membrane, thylakoid membrane of cholorplasts
• ABC superfamily: Bacterial plasma membranes (amino acid, sugar, and peptide transporters, mammalian plasma membranes(transporters)

ABC Transporters

• Transmembrane proteins using ATP hydrolysis energy to translocate various substances
• They transport sugars, amino acids, ions, peptides, hormones, etc.
• In humans, ABC transporters are found in the liver, blood-brain barrier, kidney, and intestine.
• Eukaryotic ABC transporters are exporters

E. coli ABC Transporter

• The E. coli ABC Transporter is found in the outer membrane, periplasmic space, and inner membrane.
• ABC transporters bind to periplasmic substrate-binding proteins with bound solutes

Multidrug Resistance (MDR) Transport Protein/P-Glycoprotein

• It is an active ABC transporter that transports anticancer drugs.

P. falciparum Resistance to Chloroquine

• P. falciparum has evolved complex mechanisms to confer resistance to antimalarial drugs like chloroquine.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

• CFTR serves as an ABC transporter controlling ion flow
• Its dysfunction leads to cystic fibrosis

Channel Proteins

• Form hydrophilic pores through membranes, for inorganic ion transport
• Operate through passive transport

Properties of Ion Channels

• Ion selectivity ensures only correct size and charged ions can pass.
• They are not always open, but gated

Types of Channels (Based on Stimulus)

• Ligand-gated channels open in response to certain molecules (neurotransmitters).
• Mechanically-gated channels open due to physical forces
• Voltage-gated channels open when at a certain membrane potential

Resting Membrane Potential

• Resting membrane potential is the state in which there is no net flow of ions across the plasma membrane
• Action potential is the state when an electrical charge travels along excitation or nerve impulse
• Depolarization of the plasma membrane is triggered during action potentials, causing a shift in membrane potential to a less negative value

Neurons

• Neurons receive, conduct and transmit signals
• Electrical signals are collected by dentrites and transferred to the axon
• There, electrical signals are passed to dendrites of another cell or an effective cell

Voltage-gated Na+ Channels

• At resting potential, the channels are closed
• When a nerve impulse occurs, the gate opens for N+ entry
• For a short period following entry, the channel cannot reopen again

Voltage-Gated Ions

• Mutations in voltage-gated Na+ channels expressed in the heart cause ventricular fibrillation and heart attacks.
• Mutations in other Na+ channels mainly expressed in the brain, cause epilepsy and febrile seizures

Transmitter-Gated Ion Channels

• Neurotransmitters are small signal molecules (e.g., acetylcholine) stored in vesicles, released by exocytosis
• Synapses are junctions where neurons release a chemical neurotransmitter on a postsynaptic target cell

Transport of Neurotransmitters

• Neurotransmitters are transported into synaptic vesicles by H-linked antiport proteins.
• Vesicles have a diameter of 40-50 nm, and their lumen maintains a low pH via V-class proton pumps.

Acetylcholine Receptors

• Transmitter-gated ion channel
• Opens when in the presence of acetylcholine

Neurotransmitters Convert Chemical Signals to Electrical Ones at Chemical Synapses

• This is done through H+-linked antiporters
• Via V-class, Ca2+, neurotransmitter symport proteins

Neurotransmitters

• Excitatory ones (acetylcholine, serotonin, glutamate) open cation channels, causing Na+ influx, depolarizing the postsynaptic membrane.
• Inhibitory neurotransmitters (GABA, glycine) open Cl- or K+ channels, suppressing firing by making it harder to depolarize the postsynaptic membrane

Transmitter-Gated Ion Channels as Drug Targets

• Curare blocks acetylcholine receptors on muscles

Drugs and Transporters

• Valium/Librium bind to GABA receptors, enhancing GABA's inhibitory action by allowing Cl- channels to open at lower neurotransmitter concentrations
• Prozac inhibits serotonin uptake
• Strychnine (a pesticide) blocks glycine receptors, causing muscle spasms, convulsions, and death

Importance of Transporters for Drugs

• SERT/5HTT (sodium-dependent serotonin transporters) is a target for major antidepressant drugs, the selective serotonin reuptake inhibitors (SSTIs).
• Transporters can either increase or decrease the uptake and efflux of drugs
• Transporters also work against drugs by causing over expression of Multidrug resistant proteins