Lipids and Membranes - Comprehensive Notes

Lipids and Membranes

Learning Objectives

• Describe the structure of lipids and the significance of the lipid bilayer.

• Distinguish the different types of membrane proteins.

• Summarize the features of the fluid mosaic model.

• Explain movement of ions and membrane potential.

• Describe different types of transport systems.

Fatty Acids

• Simplest lipids are fatty acids.

• They are long-chain carboxylic acids.

• At physiologic pH, they are ionized to carboxylate form.

Types of Fatty Acids

• Most common fatty acids are even-numbered:

  • C16 = Palmitate

  • C18 = Stearate

• Saturated: tail Cs saturated with H

• Unsaturated: tail Cs have 1 or more double bonds (usually cis)

Triacylglycerols (Triglycerides)

• Fats and oils found in animals and plants are triacylglycerols.

• Acyl groups (R-CO-) of 3 FAs are esterified to the 3 OH groups of glycerol.

Ester Bond Formation

• Ester bond links each acyl group through a condensation reaction.

• Lipids do not form long chains like other biomolecules.

• They cannot be linked end-to-end to form long chains.

Glycerophospholipids

• Contain a glycerol backbone with:

  • Fatty acyl groups esterified at positions 1 and 2

  • A phosphate derivative esterified at position 3 (head group)

• Major lipids of biological membranes

• Lipids are usually named according to the head group.

Examples of Glycerophospholipids

• Phosphatidylcholine

  O=P-O-CH2-CH2-N(CH3)3

• Phosphatidylethanolamine

  O=P-O-CH2-CH2-NH_3

• Phosphatidylglycerol

  O=P-O-CH2-CHOH-CH2OH

• Phosphatidylserine

  O=P-O-CH2-CH(NH3)-COO

Properties of Glycerophospholipids

• Not completely hydrophobic; they are amphipathic.

• Have hydrophobic tails attached to polar or charged head groups.

• Structure is ideal for forming bilayers.

• Bonds can be hydrolyzed by phospholipases.

Phospholipases

• Phospholipase A1

• Phospholipase A2

• Phospholipase C

• Phospholipase D

Sphingomyelins

• Have phosphocholine or phosphoethanolamine head groups.

• Sterically similar to their glycerophospholipid counterparts

• Major difference: sphingosine backbone

• Sphingosine is a derivative of serine and palmitate.

• Ceramide: Fatty acid attached to sphingosine via an amide bond to serine.

• Sphingomyelin: Ceramide with a head group like phosphocholine or phosphoethanolamine.

Sphingolipids

• Some sphingolipids have sugar head groups instead of phosphate:

  • Cerebrosides: have one sugar

  • Gangliosides: have more complex sugars

Cholesterol

• A 27-carbon, four-ring molecule

• Important component of cell membranes

• Metabolic precursor of steroid hormones (Estrogen and testosterone)

Lipid Bilayer

• Fundamental component of a biological membrane

• 2D array of amphipathic molecules out of contact with water

• Tails associate with each other

• Head groups interact with the aqueous solvent

Lipid Bilayer Formation

• Glycerophospholipids and sphingolipids have two tails and a big head, making them perfect for forming bilayers in membranes.

• Fatty acids, being small and amphipathic, form micelles (tiny spheres), not bilayers.

• Triacylglycerols and cholesterol are mostly nonpolar, so they can't form bilayers alone, but can be found inside membranes.

Membrane Proteins

• Lipid bilayer: barrier to the diffusion of polar substances

• Additional functions of a biological membrane depend on membrane proteins

  • Integral membrane proteins: span the entire membrane. Require detergent to remove.

  • Peripheral proteins: found in inner or outer leaflet. Have loose attachment.

  • Lipid-linked proteins: anchored in the lipid bilayer by a covalently attached lipid group

Fluid Mosaic Model

• Described in 1972 by Jonathan Singer and Garth Nicolson

• Membrane proteins are like icebergs floating in a lipid sea

• Mosaic because it's made of:

  • Lipids (form the bilayer)

  • Proteins (some stick out, some go through)

  • Carbohydrates (attached to lipids or proteins, mostly outside)

• Fluid because lipids and many proteins can move laterally (like liquid), giving the membrane flexibility

Cell Membrane Composition

• Guardian of the Cell: divides the body into ECF and ICF

• 55% Proteins

• 25% Phospholipids

  • Outer Leaflet: Phosphatidylcholine, Sphingomyelin

  • Inner Leaflet: Phosphatidylethanolamine, Phosphatidylserine, Phosphatidylinositol

• 13% Cholesterol (gives membrane fluidity)

• 4% Other lipids (glycolipids)

• 3% Carbohydrates

• Glycocalyx: loose carbohydrate coat of cell surface

Cell Membrane Permeability and Potential

• More permeable to K^+ than Na^+

• Inside the cell: Low Na^+, high K^+}

• Outside the cell: High Na^+, low K^+

• Charge imbalance generates a voltage across the membrane = MEMBRANE POTENTIAL or \Delta\psi

• \Delta\psi = \psi{inside} - \psi{outside}

Membrane Potential Calculation

• R = gas constant = 8.3145 J⋅K⁻¹⋅mol⁻¹

• T = temperature in Kelvin (20°C = 293 K)

• Z = net charge per ion

• F = Faraday constant or the charge of one mole of electrons = 96,485 coulombs⋅mol⁻¹ or 96,485 J⋅V⁻¹⋅mol⁻¹

• \Delta\psi is expressed in units of volts (V) or millivolts (mV)

Nernst Equation

\Delta\psi = 0.058 V log{10} \frac{[ion]{in}}{[ion]_{out}}

Example Problem

Calculate the intracellular concentration of Na^+ when the extracellular concentration is 160 mM. Assume that the membrane potential, -50 mV at 20°C, is due entirely to Na^+.

Solution

Using the Nernst Equation:

\Delta\psi = 0.058 V log{10} \frac{[Na^+]{in}}{[Na^+]_{out}}

log{10} \frac{[Na^+]{in}}{[Na^+]_{out}} = \frac{\Delta\psi}{0.058 V}

log [Na^+]{in} = \frac{\Delta\psi}{0.058 V} + log [Na^+]{out}

log [Na^+]_{in} = \frac{-0.050 V}{0.058 V} + log(0.160)

log [Na^+]_{in} = -0.862 - 0.796

log [Na^+]_{in} = -1.66

[Na^+]_{in} = 0.022 M = 22 mM

Action Potential

• Most animal cells maintain a membrane potential of about -70 mV.

• The negative sign indicates that the inside (cytosol) is more negative than the outside (ECF).

• When a nerve is triggered: Na^+ channels open, and Na^+ rushes into the cell because there’s more Na^+ outside.

• This makes the inside more positive, changing the voltage from -70 mV to +50 mV. This change is called an action potential.

Action Potential Mechanism

• Action potential triggers the opening of nearby voltage-gated K^+ channels.

• These channels open only in response to the change in membrane potential.

• The open K^+ channels allow K^+ ions to diffuse out of the cell, following their concentration gradient.

• This action restores the membrane potential to about -70 mV

Propagation of Action Potential

• Action potential also stimulates the opening of additional Na^+ channels farther along the axon (the elongated portion of the cell).

• This induces another round of depolarization and repolarization, and then another.

• In this way, the action potential travels down the axon.

Directionality of Action Potential

• The signal cannot travel backward because once the ion channels have shut, they remain closed for a few milliseconds.

• The action potential travels in only one direction because previously open channels remain closed.

Cell Transport

• Lipid soluble (non-polar) substances can cross the cell membrane easily (simple diffusion)

  • Steroids

  • Lipids

  • O2

  • CO2, and N2

  • Numerous drugs and anesthetic gases

Simple Diffusion

• No carrier/protein transporter

• No energy required (passive)

• Follows gradient

• Driven by transmembrane concentration gradient (substances diffuse down their concentration gradient)

Impermeable Substances

• Water-soluble substances are repelled by the lipid bilayer

  • Charged molecules (H₂O, Na^+,Cl^-, K^+, glucose)

  • Large particles (proteins)

Carrier-Mediated Transport

• Has carrier/protein transporter

• Conducted via protein

• Can be saturated → can reach a transport maximum (T_m)

• Can experience competition

• Types include:

  • Facilitated diffusion

  • Primary active transport

  • Secondary active transport

Facilitated Diffusion

• Has carrier/protein transporter

• No energy required (passive)

• Follows gradient

• Driven by transmembrane concentration gradient

• Almost any substance that cannot enter via simple diffusion can use facilitated diffusion.

Primary Active Transport

• ATP energy required (active)

• Examples end with, “ATPase” (Na^+/K^+-ATPase, H^+-ATPase, and Ca^{2+}-ATPase)

• Moves against gradient

• Transported substances move energetically uphill, against their electrochemical gradient.

• Has carrier/protein transporter

Secondary Active Transport

• ATP energy required (active) - ATP required indirectly, only to keep intracellular Na^+ low via the Na-K pump

• Moves against gradient but follows Na^+ gradient created by primary active transport

• Can be symporters or antiporters

  • Symporters include: Na^+-glucose cotransporter, Na^+-amino acid cotransporter

  • Antiporters include: Na^+-Ca^{2+} exchange and Na^+-H^+ exchange

• Has carrier/protein transporter

Receptor-Mediated Endocytosis

• Proteins on ligand bind to proteins on cell surface → cell membrane forms coated vesicle that is then ingested.

• High yield examples include:

  • Iron in the serum (transferrin-iron complex stimulate endocytosis)

  • LDL stimulates LDLR

  • EGF stimulates EGFR

Membrane Fusion

• Multistep process that begins with the targeting of one membrane (for example, the vesicle) to another (for example, the plasma membrane)

• Final steps in the transmission of a signal from one neuron to the next, or to a gland or muscle cell, culminate in the release of substances known as neurotransmitters

  • e.g. Acetycholine (stored in membrane-bounded compartments or synaptic vesicles)

Acetylcholine Release

1. When an action potential reaches the axon terminus, it causes voltage-gated Ca^{2+} channels to open.

2. The increase in intracellular Ca^{2+} ion concentration triggers the fusion of synaptic vesicles with the plasma membrane so that the neurotransmitter acetylcholine is released into the synaptic cleft.

3. Acetylcholine binding to receptors on the surface of the muscle cell leads to muscle contraction. The signal is short-lived because acetylcholine remaining in the synaptic cleft is rapidly degraded.

Serotonin Signaling

• Neurotransmitter serotonin, a derivative of tryptophan, is released by cells in the central nervous system

• Serotonin signaling leads to feelings of well-being, suppression of appetite, and wakefulness

• Unlike ACh, serotonin is not broken down in the synapse

• About 90% of it is transported back into the cell that released it and is reused.

References

• Garrett, Reginald H. & Grishham Charles M. - Biochemistry, 7th edition (2023), Cengage Learning, Boston MA 02210, USA.

• Physeo. (2024). Physeo Physiology: General Principles.

• Pratt, Charlotte & Cornely, Kathleen - Essential Biochemistry, 5th edition (2021), John Wiley and Sons Singapore Pte. Ltd