Passive and Membrane Transport

Passive Transport Overview

• Lecture slides marked with an exclamation contain critical information for tests/exams.
• Passive transport is explored through biological membranes
• Other topics include pH-dependent partitioning, facilitated diffusion, ion channels, and gap junctions.
• Passive transport also covers diffusion, hydrophobic molecule transport, and lipid-water partition coefficient; anesthetics, TDDS (Transdermal Drug Delivery Systems), and liposomes also play key roles.

Membrane Transport Classification

• Membrane structure includes lipid bilayers or complete biological membranes in one or two layers
• Energetics distinguishes passive transport (simple/facilitated diffusion) from active transport (primary/secondary)
• Transport categorisation depends on the number and direction of transported substances (uniport, symport, antiport) and solubility (hydrophilic/hydrophobic)
• R = C(l) / C(w) stands for the partitioning coefficient where l and w refer to lipid and water

Passive vs. Active Transport

• Passive occurs along electrochemical gradient
• Active happens against electrochemical gradient

Simple Diffusion Factors

• Rate is determined by concentration gradient, charge/membrane potential, total electrochemical potential difference, and permeability
• Rate is calculated as P = R * D(l) / d, where P is permeability, R is the lipid-water partition coefficient, D(l) is diffusion constant, and d is membrane thickness

Fick's Law

• Fick's Law, which models diffusion processes, typically includes equations that address the movement of charged particles, emphasizing their behavior across concentration gradients.
• Modified for cell membranes considering permeability, area, concentration difference, charge, and water-lipid partitioning
• Variables include permeability, water-lipid partition coefficient, diffusion constant, and membrane thickness.

Diffusion in the Body

• Gas exchange in alveoli is an example in the Lungs
• Reabsorption in renal tubules is an example in the Kidneys

Hydrophobic Molecules

• Passive depends on the molecule's lipid/water partition coefficient (R)
• Hydrophobicity means R > 1
• Henderson-Hasselbalch equation calculates the concentrations of protonated and unprotonated forms relative to pH and pKa.

Lipid-Water Partition Coefficient (R)

• For small, non-charged molecules, R determines the accumulation in cell membranes
• Higher R results in higher concentration in the membrane/cytosol
• General anesthetics effectiveness is proportional to R; lipid solubility matters

General Anesthetics

• Embedding general anaesthetics in the membrane increases lateral pressure and activates phospholipase D to generate phosphatidic acid
• This process can activate K+ channels and cause hyperpolarization
• Ether in the cell membrane activates K+ channels
• Hydrostatic pressure reverses this effect by expelling ether molecules

Anesthetics and Receptors

• Group 1, intravenous (etomidate, propofol, barbiturates), acts on GABA(A) receptors (chloride channels)
• Group 2, inhaled (ketamine, N₂O, Xenon, cyclopropane), inhibits NMDA receptors and activates leak K+ channels
• Group 3, inhaled (halothane, flurane, isoflurane, sevoflurane, desflurane), activates GABA(A) and leak K+ channels while inhibiting NMDAR, nAChR, mKATP, SR3, Nav Channels and HCN channels

TDDS

• Transdermal drug delivery systems are topical/transdermal for hydrophobic drug transfer
• Stratum corneum barrier is surpassed when drugs have high lipid-water partition coefficient (increased with prevented evaporation)
• Factors include skin permeability, surface area, blood/lymphatic supply etc
• Transdermal patches can be easily removed and provide comfortable, controlled delivery

Liposomes

• These work by fusing with cell membranes to deliver a non-specific uptake for cancer-therapy and vaccination

pH-Dependent Partitioning

• The Henderson-Hasselbalch equation is a fundamental relationship in biochemistry and pharmacology that describes the relationship between the pH of a solution, the pKa of a weak acid or base, and the ratio of the ionized and unionized forms of amphiphilic substances. This equation is crucial for predicting how these materials will distribute themselves in different environments within the body.
• Lysosomotropic amines are a class of compounds that preferentially localize in lysosomes, which are membrane-bound organelles that maintain an acidic environment. The ionization of these amines is influenced by the low pH, leading to their accumulation due to the pH-dependent partitioning where the charged form is trapped within the lysosome.
• Such drug sequestration can have deleterious effects on cellular function, as it can alter the pharmacokinetics of the drug. Local anesthetics, particularly lidocaine, serve as pertinent examples, wherein their accumulation in lysosomes can impact their efficacy and safety profile.

Local Anesthetics

• They include bupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, and tetracaine.
• Local anesthetics block sodium channels from the intracellular side and suppress neuronal excitability
• Lidocaine has higher levels of cell penetration when the extracellular space is acidic

Daunorubicin

• Daunorubicin accumulation in lysosomes accumulates because it is an amine that accumulates in acidic lysosomes as a DNA-intercalating cancer drug.
• Effectiveness is reduced by sequestering action in the lysosomes

Facilitated Diffusion

• Process moves molecules along the electrochemical gradient without energy
• Transporter molecules bind specifically to transported molecules
• GLUT1-5 transporters, for example, bind D-glucose but not the L isomeric variant

Facilitated Diffusion cont.

• Transport rate is limited by the number and rate of transfer of transport molecules
• Specific antagonists can inhibit it (unlike simple diffusion)

Glucose Transporters (GLUTs)

• Glucose uniport into cells is facilitated by GLUT proteins.
• Expression varies by tissue; GLUT3 in the brain, GLUT2 in liver and intestine, GLUT4 in muscle and fatty tissue

Ion Channels

• Selective pores facilitate ion diffusion down electrochemical gradients
• Facilitated diffusion rate is very effective for intracellular ion concentration regulation
• Controlled, or gated, opening acts as a signaling switch for AP generation and calcium-level elevation

Types of Ion Channels

• Include voltage-gated and ligand-gated
• Other types comprise IC signal-gated and G-protein-gated
• Stretch/mechanically-gated Leak/background channels (always open) also exist

Gap Junction Diffusion

• Small molecules below 2 kDa, both polar and non-polar can travel through the cell
• EM* images demonstrate what the process looks like on a microscopic level
• Examples of substances include ATP, ADP, cAMP, IP3, Ca2+, etc

Intercellular Trafficking

• Gap junction channels (GJC) mediate intercellular communication via connexins or connexons
• Connexons make hemichannels to transport signals

Gap Junctions

• GJC closure is induced by dopamine via increased intracellular calcium, as well as high H+ concentration (low pH) via the ball-and-chain model
• Voltage-gating in cardiac cells and phosphorylation modulate GJC conductivity and assembly

Keywords

• Relevant terms include being apolar/nonpolar, polar, amphipatic molecule, and more
• Facilitated diffusion, passive transport, and how lipid-water partitioning coefficients contribute
• Glucose uniport, ion channel gating/selectivity, gap junctions, plus connexins, GJC, and voltage sensors further inform the topic

Explore passive transport through biological membranes, covering diffusion, hydrophobic molecule transport, and more. Differentiate between passive and active transport based on energetics. Also study transport categorization based on substances and solubility.