Passive Transport in Biological Membranes

• Passive transport through cell membranes reviewed lecture content
• Key topics include classification of membrane transports, passive transport in biological membranes, diffusion, and transport of hydrophobic molecules
• The content explores pH-dependent partitioning, facilitated diffusion, ion channels, and gap junctions, as well as the pharmacological aspects related to anesthetics, TDDS, and liposomes

Classification of Membrane Transport

• Membrane structure dictates whether transport occurs through a lipid bilayer or a more complex biological membrane, and how many layers are involved
• Energetics classifies transport as passive (simple or facilitated diffusion) or active (primary or secondary)
• Transport is also categorized by the number of substances moved (uniport, symport, antiport) and the substance's solubility (hydrophilic, hydrophobic)

Real (Biological) Membranes

• Passive transport occurs along an electrochemical gradient
• Active transport happen against an electrochemical gradient
• Use "Electrochemical gradient" for charged particles because "concentration gradient" is not exact

Simple Passive Diffusion

• Rate of diffusion through a membrane is determined by concentration gradient, charge, membrane potential, and a permeability constant
• R is the lipid-water partition coefficient (hydrophobic vs. hydrophilic)
• D₁ is a constant in lipid membrane
• d is membrane thickness

Fick's Laws of Diffusion

• Fick's 1st Law defines diffusion in general, and also describes charged particles
• Fick's Law describes diffusion through a cell membrane as a relationship to molecule permeability (Px), concentration difference (Δcx), and an electrical potential term
• PX is the permeability of molecule X through the membrane; a ratio of Rx (water–lipid partition coefficient), DL (diffusion coefficient), and d (membrane thickness).

Passive Diffusion Examples in Humans

• Gas exchange in alveoli and reabsorption in renal tubules.

Transport of Hydrophobic Molecules

• Passive transport depends on R, the lipid/water partition coefficient
• Hydrophobic molecules have R > 1

Henderson-Hasselbalch Equation

• The Henderson-Hasselbalch equation determines partition
• It relates pH to pKa and the concentrations of neutral [M] and charged forms [M+]
• The formula is pH = pKa + log([M]/[M+]) or log([M]/[M+]) = pH - pKa
• When pH > pKa, [M] > [M+], meaning a more neutral form exists
• When pH < pKa, [M] < [M+], meaning a more charged form exists
• When pH = pKa, then [M] = [M+]

Lipid-Water Partition Coefficient (R)

• Defines accumulation in the membrane and inside the cell for small, non-charged molecules
• Higher R indicates greater concentration

General Anesthetics

• General anesthetics change the gating of ion channels and/or activate enzymes
• This results in phosphatidic acid generation, which may activate K+ channels and cause hyperpolarization.
• They are lipid soluble, and their efficacy is linked to their R value
• They affect receptors (e.g., GABA, glutamate receptor) and ion channels (e.g., K+ leak) in the cell membrane
• Specific examples across groups include intravenous and inhalational anesthetics, with diverse effects on chloride channels, NMDA receptors, and various ion channels

TDDS (Transdermal Drug Delivery System)

• TDDS involves transdermal exposure via ointments, creams, or patches
• Skin is permeable to hydrophobic molecules
• TDDS uses a large surface area and good blood/lymphatic supply
• The stratum corneum is the key barrier at ~10 µm of dead, keratin-filled cells
• Drugs with a high lipid-water partition coefficient are delivered via comfortable, controlled patches
• The significant transport of drugs with high lipid-water partition coefficient (R), can be increased by preventing the evaporation

Liposomes in medicine

• Liposomes work through fusion with the cell membrane for non-specific uptake in cancer therapy and vaccination

pH Dependent Partitioning

• Uses the Henderson-Hasselbalch equation to determine intracellular distribution of amphiphilic molecules

"Lysosomotropic Amines"

• "Lysosomotropic amines" accumulate in lysosomes
• They passively diffuse across lipid bilayers and become ionized in lysosomes
• This accumulation can be harmful and affect drug efficacy
• Examples are lidocaine, and cytostatic drugs

Local Anesthetics: pH, pKa

• Local anesthetics include bupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine
• They block sodium channels from the intracellular side, suppressing neuronal excitability
• Acidic extracellular spaces enhance lidocaine penetration, whereas bupivacaine protonates more

Daunorubicin

• Daunorubicin: a DNA-intercalating drug for cancer treatment that is an amine that can be protonated
• Daunorubicin accumulates in lysosomes
• This reduces its nuclear effects in tumor cells

Facilitated Diffusion

• This is the movement of a molecule across the cellular membrane using trans-membrane protein
• Occurs without energy expenditure, along the electrochemical gradient
• Transporter is needed that specifically binds the molecule to be transported
• i.e. GLUT1-5 uniporters binds D- glucose
• Not L isomeric variant, or ion channels are selective for certain type of ions)-
• The rate is limited by the number of transporting molecules
• It can be inhibited by specific antagonists, i.e. TTX for Nav channels

Glucose Transporters (GLUTs)

• Mediates glucose uniport into cells

Ion Channels

• Ion channels selectively allows facilitated diffusion
• selective pores for the given type(s) of ions
• This follows the electrochemical gradient
• Ion channels have a very high transport rate
• Effective at regulation of the intercellular ion concentration relative to membrane potential
• Controlled gated opening
• This is a switch in the signaling process, remember AP generation

Ion Channel Types include

• Voltage-gated, Ligand-gated, IC signal-gated and Stretch/mechanically-gated
• G-protein (7-TM receptor) gated
• Leak/background channels (always open)

Gap Junctions

• Gap Junctions transport molecules between cells -diffusion of molecules across cell membranes (fluorescent dye)
• Permeable to small molecules, both polar and non-polar
• For example, ATP, ADP, cAMP, IP3, Ca2+, glutamate, glutathione, Na+, K+, Cl-
• They are facilitated by connexion in the plasma membrane

Regulation of Gap Junction Channels:

• Dopamine increases Calcium presence which closes Gap Junction Channels
• High Hydrogen presence closes Gap Junction Channels
• Voltage Gating of cardiac cannels reduces conductivity
• Connexins or connexons are affected

Keywords:

• Apolar/nonpolar
• Polar
• Facilitated diffusion
• Passive Transport
• Glucose Uniport
• Ion Channel gating
• Ion Channel selectivity
• Gap Junction
• Voltage sensor

Covers passive transport through cell membranes, including diffusion and transport of hydrophobic molecules. Explores pH-dependent partitioning, facilitated diffusion, ion channels, and gap junctions. Also discusses pharmacological aspects like anesthetics and liposomes.