Plasma Membrane

Eukaryotic Cells

  • Definition: Cells containing a nucleus

  • Major compartments:

    • Cytoplasm:

    • Part of the cell outside the nucleus.

    • Contains:

      • Cytoplasmic Matrix: An aqueous gel.

      • Organelles: Special subcellular structures performing specific functions (e.g. genetic information storage, energy production).

      • Cytoskeleton: Structural framework of the cell.

      • Inclusions: Various non-functioning components.

    • Nucleus:

    • Largest organelle.

    • Contains the genome and necessary enzymes for DNA replication and RNA transcription.

  • Examples of organelles:

    • Nuclei: Store genetic information.

    • Mitochondria: Produce chemical energy.

    • Ribosomes: Assemble proteins.

  • Organelles are suspended in the cytoplasm except for the plasma membrane, which surrounds the cytoplasm.

Organelles

  • Membranous Organelles (with membranes):

    • Endoplasmic Reticulum (Rough and Smooth)

    • Golgi Apparatus

    • Endosomes

    • Lysosomes

  • Non-Membranous Organelles (without membranes):

    • Microtubules

    • Actin Filaments

    • Intermediate Filaments

    • Transport Vesicles

    • Mitochondria

    • Peroxisomes

    • Centrioles

    • Ribosomes

    • Proteasomes

Plasma Membrane - Overview

  • Definition:

    • The plasma membrane is the thin, flexible outer boundary of a cell, primarily composed of a phospholipid bilayer, which acts as a barrier between the internal and external environments.

  • Critical Functions:

    • Protects the cell's contents.

    • Regulates the passage of substances (selective permeability).

    • Facilitates communication with surroundings.

  • Composition:

    • Phospholipid Bilayer: Embedded with:
      1) Proteins (transport and signaling)
      2) Cholesterol (regulates membrane fluidity)
      3) Carbohydrates (attached to lipids and proteins) forming Glycocalyx

  • Structure:

    • Approximately 7.5 nm thick.

    • Inner leaflet faces cytoplasm (p-face); outer leaflet faces extracellular space (e-face).

    • Membranes covering organelles are phospholipid bilayers, forming compartments for specific biochemical processes.

Unit Membrane

  • Fundamental Structural Unit:

    • Consists of a phospholipid bilayer sandwiched between two protein layers.

  • Fluid Mosaic Model:

    • Supersedes unit membrane model; proteins are embedded rather than forming continuous layers.

  • Trilaminar Structure:

    • Observed under a transmission electron microscope after fixation with osmium tetroxide.

    • Reacts with unsaturated fatty acids’ double bonds but not with non-polar saturated fatty acid tails.

    • Designated as "unit membrane" due to this appearance.

Plasma Membrane - Molecular Structure

  • Fluid Mosaic Model components:
    1) Phospholipid Bilayer
    2) Embedded and Attached Proteins
    3) Cholesterol
    4) Carbohydrates

  • Lipid Bilayer:

    • Composed mainly of:

    • Phospholipids

    • Glycolipids

    • Cholesterol

    • Permeability:

    • Permeable to small non-polar molecules and lipid-soluble molecules.

    • Impermeable to large polar molecules and charged ions.

Membrane Phospholipids

  • Amphipathic Nature:

    • Contains hydrophilic (polar) head and hydrophobic (nonpolar) fatty acyl tails (one usually unsaturated).

  • Orientation:

    • Polar head faces the surface of the membrane.

    • Fatty acyl tails project into the interior, forming weak non-covalent bonds between both leaflets.

Glycolipids and Cholesterol

  • Glycolipids:

    • Found in the extracellular part of the outer leaflet; polar carbohydrate residues contribute to the glycocalyx.

  • Cholesterol:

    • Comprises 2% of membrane lipids.

    • Maintains structural integrity of the membrane.

    • Forms lipid rafts: microdomains rich in cholesterol and glycosphingolipids, which are less fluid and thicker than surrounding membranes.

Membrane Proteins

  • Types of Membrane Proteins:

    • Integral Proteins: Embedded permanently into the membrane.

    • Peripheral Proteins: Transiently associated with membrane surfaces.

  • Composition:

    • Constitute approximately 50% of the plasma membrane.

Membrane Fluidity

  • Importance: Crucial for exocytosis, endocytosis, membrane trafficking, and membrane biogenesis.

  • Decreases with:

    • Lower temperatures

    • Saturation of fatty acyl tails

    • Increased cholesterol content

  • Definition:

    • The ability of phospholipids and proteins within a cell membrane to move and change positions, likened to a “flowing sea”.

  • Lateral Motion: Membrane proteins may move laterally, compared to icebergs floating in lipid seas.

Transmembrane Proteins

  • Structure:

    • Includes hydrophilic and hydrophobic amino acids; some are multi-pass proteins traversing the plasma membrane.

  • Functions:
    1) Pumps: For substance transport.
    2) Channel Proteins: Allow small ions, molecules, and water passage.
    3) Receptors: For ligand recognition and localized binding.
    4) Linker Proteins: Anchor intracellular cytoskeleton to extracellular matrix (e.g., Integrins).
    5) Enzymes: Catalyze reactions near the membrane.
    6) Structural Proteins: Form junctions (e.g., desmosomes) with neighboring cells.

Freeze Fracture Technique

  • Definition: Rapid freezing and mechanical fracturing technique revealing membrane structures.

  • Faces:

    • E-face: Backed by extracellular space

    • P-face: Backed by cytoplasm, displaying more proteins than the E-face due to preferential attachment of integral proteins.

Peripheral Proteins

  • Characteristics:

    • Loosely associated, involved in cell signaling and linking to other proteins.

  • Characteristics:

    • Do not extend into the lipid bilayer.

    • Located on cytoplasmic and extracellular parts of the membrane.

    • Glycoproteins: Carbohydrates binding to peripheral proteins on the extracellular aspect.

  • Functions of Peripheral Proteins:
    1) Act as electron carriers (e.g., cytochrome C).
    2) Part of the cytoskeleton.
    3) Involved in intracellular second messenger systems.

Summary of Membrane Protein Characteristics

  • Classifications:
    1) Integral (permanent) and Peripheral (transient).
    2) Functions include transporters, receptors, enzymes, structural support.
    3) Lipid-to-protein ratio ranges from 1:1 in most cells to 4:1 in myelin.
    4) Some proteins diffuse laterally while others remain immobile, anchored by cytoskeletal components.

Glycocalyx - Cell Coat

  • Definition:

    • A carbohydrate-rich gel-like layer on cell surfaces, located on the outer surface.

  • Composition:
    1) Polar oligosaccharide side chains linked covalently to proteins (glycoproteins) and lipids (glycolipids).
    2) Proteoglycans (glycosaminoglycans bound to integral proteins).

  • Function:

    • Cell adhesion, recognition, and serving as receptor sites for hormones.

Lipid Rafts

  • Definition: Localized regions with high cholesterol and glycosphingolipid concentrations; thicker and less fluid than surrounding membranes.

  • Role: Acts as “signaling platforms” or domains.

  • Types:

    • Planar Lipid Rafts: Contain flotillins, engage in recruitment of specific membrane proteins and signaling pathways.

    • Caveolar Lipid Rafts (caveolae): Contain caveolins, bind cholesterol and various proteins to facilitate signal transduction.

Membrane Transport

  • Definition: Regulated movement across a cell’s lipid bilayer controlling molecular entry and exit.

  • Types of Transport:

    • Uniport: Transport of a single molecule.

    • Cotransport: Transport of two different molecules:

    • Symport: Same direction.

    • Antiport: Opposite direction.

  • Membrane Transport Proteins:

    • Facilitate movement of aqueous molecules and ions across the plasmalemma using:

    • Channel Proteins

    • Carrier Proteins

Passive Transport

  • Definition: Movement across the plasma membrane without energy required.

  • Mechanism: Molecules move down a concentration or electrochemical gradient.

  • Includes:

    • Simple diffusion

    • Facilitated diffusion

Active Transport

  • Definition: Requires energy; transports molecules against an electrochemical gradient via carrier proteins.

Types of Diffusion

  • 1) Simple Diffusion:

    • Involves small nonpolar molecules (e.g., O$2$, N$2$) and small uncharged polar molecules (e.g., H$2$O, CO$2$, glycerol).

    • Exhibits little specificity; rate proportional to concentration gradient.

  • 2) Facilitated Diffusion:

    • Exhibits specificity for transported molecules.

    • Faster than simple diffusion.

    • Pathways include:
      1) Ion Channel Proteins
      2) Carrier Proteins
      3) Aquaporins

Ion Channel Proteins

  • Definition: Multi-pass transmembrane proteins forming small aqueous pores across membranes.

  • Function: Transport specific small water-soluble molecules and ions (e.g., Chloride) down electrochemical gradients (passive transport).

Carrier Proteins

  • Definition: Multi-pass transmembrane proteins undergoing reversible conformational changes.

  • Function: Transport specific molecules across the membrane in both passive and active transport modes.

Aquaporins

  • Function: Permit rapid water transport across cell membranes.

Na+/K+ Pump

  • Mechanism: Involves antiport transport of Na$^+$ and K$^+$ ions mediated by Na+/K+ Adenosine triphosphatase (ATPase).

  • Transport Details:

    • Pump three Na$^+$ out and two K$^+$ into the cell.

    • Hydrolysis of one ATP molecule transports five ions.

  • Function: Maintain a constant cell volume by lowering intracellular Na+ concentration, thereby decreasing osmotic pressure and reducing water influx.

Glucose Transport

  • Mechanism: Involves symport movement of glucose across epithelial membranes (trans-epithelial transport).

  • Energy Source: Often powered by an electrochemical Na+ gradient.

ABC Transporters

  • Definition: Transmembrane proteins with:

    • Nucleotide-binding domain (intracellular)

    • Membrane-spanning domain (transmembrane).

  • Function: Export materials (toxins, drugs) from the cytoplasm to extracellular space using ATP; e.g., protect developing fetus from xenobiotics.

Facilitated Diffusion of Ions

  • Mechanisms:

    • Ion channel proteins or ionophores that form complexes with ions to transport across the membrane.

    • Methods:

    • Enfold the ion and pass through lipid bilayer.

    • Form an ion channel whose lumen is hydrophilic.

Cell-to-Cell Communication

  • Definition: Involves signaling molecules and their receptors, enabling cells to exchange information via direct contact or by chemical messengers.

  • Process: Specialized signal molecules (ligands) bind to receptor proteins on target cells, initiating responses within.

Signaling Molecules

  • Examples:

    • Neurotransmitters: Released into synaptic clefts.

    • Hormones: Released into bloodstream or intercellular space (paracrine, autocrine).

  • Types:

    • Lipid-soluble: Penetrate plasma membrane, bind to cytoplasmic/nuclear receptors, activate messengers (e.g., steroid hormones).

    • Hydrophilic: Bind to cell-surface receptors, diverse physiological effects (e.g., neurotransmitters, protein hormones like insulin).

Membrane Receptors

  • Characteristics: Primarily integral membrane glycoproteins with three domains:
    1) Extracellular domain (binds signaling molecules).
    2) Transmembrane domain (passes through the lipid bilayer).
    3) Intracellular domain (contacts peripheral proteins/cellular organelles).

  • Function: Transduce extracellular contacts into intracellular events.

Types of Membrane Receptors

  • a) Channel-linked receptors: Example: Acetylcholine receptors in synapses.

  • b) Catalytic receptors: Example: Insulin receptor causing autophosphorylation in response to binding.

  • c) G protein-linked receptors: Example: β receptor for epinephrine, activating intracellular messengers.

  • d) Receptors stimulating transcription: Example: Receptors for steroid hormones.

Channel-linked Receptors

  • Function: Bind signaling molecules that temporarily open/close gates, permitting or inhibiting ion movement across the membrane (e.g., nicotinic acetylcholine receptors).

Catalytic Receptors

  • Structure: Extracellular part as a receptor, intracellular part functions as a kinase (e.g., insulin receptor).

  • Process: Cell endocytoses the insulin-receptor complex for intracellular functioning.

G Protein-Linked Receptors

  • Mechanism: Binding causes dissociation of α subunit to interact with the target or activates α and/or β and γ complexes, leading to activation of intracellular second messengers (e.g., cAMP).

G Protein-Coupled Receptors (GPCRs)

  • Definition: Largest family of cell surface receptors; convert extracellular signals into intracellular responses via heterotrimeric G proteins.

Heterotrimeric G Proteins

  • Characteristics: Make seven passes through the cell membrane. Include:

    • Gs (stimulatory), Gi (inhibitory), Gq (activator of phospholipase C), Golf (olfactory-specific), Gt (transducin), Go (opens K+ channels, closes Ca2+ channels), G12/13 (controls actin formation and migration).

Low-Molecular-Weight G Proteins

  • Definition: Small, single-chain proteins (e.g., RAS) involved in regulating:

    • Cell proliferation

    • Differentiation

    • Protein synthesis

    • Cell attachment to extracellular matrix

    • Exocytosis

    • Vesicular traffic.

Plasmalemma-Cytoskeleton Association

  • Definition: Cytoskeleton modulates cell shape, physiology, intracellular transport, secretory, and endocytic pathways via integrins.

  • Function of Integrins: Bind extracellular matrix and cytoskeletal components, crucial for sensing the environment, and controlling cell shape and motility.

  • Characteristics: Transmembrane proteins found in all animal cells except red blood cells (RBCs).

RBC Membrane and Cytoskeleton Association

  • Integration: In RBCs, membrane association with the cytoskeleton is via Band 3 proteins.

  • Components:

    • Actin, Ankyrin, Spectrin, Band 4.1 Protein.

    • Function: Band 3 enables ion exchange for bicarbonate and maintains blood pH.

Erythrocyte Cytoskeleton

  • Components:

    • Band 4.1 Protein: Stabilizes spectrin-actin complexes.

    • Ankyrin: Connects spectrin to Band 3 proteins.

    • Spectrin: Flexible protein forming tetramers for structural reinforcement.

    • Actin: Holds spectrin tetramers and forms hexagonal latticework.

Non-RBC Cytoskeleton

  • Composition: Actin and possibly fodrin serving as non-erythroid spectrin, cross-linked by α-Actinin, Vinculin, and Talin.

Organelles in Protein Synthesis and Sorting

  • Primary Organelles: Nucleus, ribosomes, ER, and Golgi apparatus.

  • Process: Nucleus transcribes DNA into mRNA, which ribosomes translate into proteins; ER assists in folding/modification, and Golgi processes/packages proteins for destination.

High Yield Topics

  • Structure: Fluid mosaic model, asymmetry of leaflets, cholesterol function.

  • Integral Proteins: Roles in transport, receptors, ion channels.

  • Peripheral Proteins: Structural and signaling roles.

  • Glycocalyx: Function in cell recognition and adhesion.

  • Specialized structures: Lipid rafts, clathrin-coated pits, caveolae for signal transduction and endocytosis.

  • Transport Mechanisms: Passive (diffusion, facilitated diffusion) and active (Na⁺/K⁺ ATPase).

  • Endocytosis: Pinocytosis, receptor-mediated, phagocytosis; Exocytosis (constitutive vs. regulated).

Clinical Correlations

  • Cystic Fibrosis: CFTR chloride channel mutation → thick secretions, lung infections.

  • Familial Hypercholesterolemia: Defective LDL receptor endocytosis.

  • Myasthenia Gravis: Autoantibodies against ACh receptor at NMJ.

  • Cholera Toxin: Increases cAMP, causes watery diarrhea.

  • HER2/neu: Overexpressed receptor tyrosine kinase in breast cancer.

  • Tight Junction Defects: Observed in conditions like celiac disease and Crohn’s disease (leaky gut).