Cell Membranes and Signalling
Cystic Fibrosis (CF)
CF affects approximately 1 in 3900 children born in Canada.
Definition: Cystic Fibrosis is one of the most common genetic diseases.
Impact: Causes progressive impairment of lung and gastrointestinal function; average lifespan is under 40 years despite improving treatments.
Cause: Mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
CFTR Function:
Acts as a membrane transport protein, pumping chloride ions (Cl^{-}) out of lung and intestinal tract cells into the mucus lining.
Produces an electrical gradient across the membrane, facilitating the movement of sodium ions (Na^{+}) into mucus.
High Na^{+} and Cl^{-}$ concentration promotes water movement via osmosis, keeping mucus moist.
Defective CFTR leads to reduced Cl^{-}$ secretion.
CF Symptoms:
In CF individuals, CFTR is defective, causing water retention in cells, leading to thick, dry mucus.
The dehydrated mucus obstructs airways, leading to chronic cough, recurrent bacterial infections (e.g., Pseudomonas aeruginosa), inflammation, and progressive lung damage.
It also impairs digestive enzyme transport, causing malabsorption and poor growth.
Current Treatments:
No cure currently exists; treatments improving.
Invasive procedures, including lung transplants, are often needed as disease progresses.
Greatest hope lies in gene therapy to insert normal CFTR genes into afflicted cells, though many technical and ethical hurdles exist. Gene therapy aims to deliver functional CFTR genes, but challenges include efficient delivery to target cells, sustained expression, and avoiding immune responses.
Membrane Structure and Function
Biological Membrane Overview
Importance of Membranes in Biology:
Membranes act as selectively permeable barriers, essential for nutrient uptake and waste elimination, defining environments for cellular processes.
Internal membranes facilitate compartmentalization and complexity in eukaryotic cells, exemplified by the nuclear envelope.
Fluid Mosaic Model of Membranes
Model Description:
Membrane structure consists of proteins suspended in a fluid lipid bilayer.
Associated with dynamic behavior; proteins and lipids exhibit movement within the bilayer, likened to the consistency of olive oil.
Lipid bilayer is less than 10 nm thick; lipid molecules vibrate and exchange places very rapidly.
Lipids in the bilayer include phospholipids, glycolipids, and cholesterol. Proteins are diverse, including integral and peripheral types.
Asymmetry:
Membrane compositions differ between the inner and outer layers—each half has distinctive functions.
Glycolipids and glycoproteins located on the external surface; components binding to cytoskeleton found on the internal side.
The distinct lipid and protein compositions of the inner and outer membrane leaflets lead to different physiological roles, for instance, signaling molecules often bind to specific external components, while internal components interact with the cytoskeleton.
Components of Membranes:
Membranes comprise various proteins involved in transport, signaling, and attachment.
Carbohydrates, typically found as glycolipids and glycoproteins on the external surface, are crucial for cell-cell recognition and adhesion.
The specific lipid-protein ratios vary by membrane type; e.g.:
Inner mitochondrial membrane: 76% protein, 24% lipid.
Plasma membrane: approximately 49% protein, 51% lipid.
Myelin: 18% protein, 82% lipid.
Experimental Evidence for the Fluid Mosaic Model
Two primary pieces of experimental evidence corroborate the model:
Membrane Fluidity: Frye and Edidin's experiment showed intermixing of human and mouse cell proteins post fusion, illustrating fluidity.
Membrane Asymmetry: Freeze-fracture technique demonstrated differences between membrane layers using electron microscopy.
Lipid Composition and Membrane Fluidity
Lipids in Membrane Structure
Lipids, particularly phospholipids, constitute the core of biological membranes.
Phospholipid Structure:
Composed of a head group linked to two hydrophobic fatty acid tails.
Amphipathic properties (having both hydrophilic and hydrophobic regions) drive membrane assembly.
Factors Influencing Membrane Fluidity
Key Influences:
Fatty Acid Composition:
Saturated fatty acids allow tight packing; unsaturated introduce kinks, spacing lipid molecules apart and increasing fluidity.
Saturated fatty acids, lacking double bonds, pack tightly and reduce fluidity. Unsaturated fatty acids, with one or more cis double bonds, create kinks that prevent tight packing, thereby increasing fluidity.
Temperature:
Higher temperatures reduce viscosity; freezing temperatures cause membranes to gel.
Organisms adapt membranes to maintain fluidity through adjusting fatty acid compositions and desaturase enzyme regulation.
Sterols and Fluidity
Sterols (e.g., Cholesterol):
Serve as fluidity buffers, maintaining membrane integrity across temperature variations.
In animal cells, cholesterol inserts between phospholipids. At warm temperatures, it restrains phospholipid movement, reducing fluidity. At cool temperatures, it prevents tight packing, maintaining fluidity. Thus, cholesterol acts as a "fluidity buffer".
Membrane Proteins
Categories of Membrane Proteins
Integral Proteins:
Embedded in the bilayer, traverse membrane, often forming channels or transporters.
Often span the entire membrane (transmembrane proteins), having hydrophobic regions interacting with the lipid tails and hydrophilic regions exposed to aqueous environments on both sides. Others are embedded only partially (monotopic).
Peripheral Proteins:
Located on the membrane surface, interact via various bonds with integral proteins or lipids.
Bind to the surface of the membrane, often interacting with integral proteins or phospholipids through non-covalent bonds (e.g., ionic bonds, hydrogen bonds). They are easily separated from the membrane without disrupting the lipid bilayer.
Functions of Membrane Proteins
Key Roles:
Transport: Allow selective movement of substances across membranes.
Enzymatic Activity: Facilitate biochemical reactions.
Signal Transduction: Enable cell to respond to external signals through receptors.
Attachment: Aid in connecting cytoskeleton elements and mediating cell-cell interactions.
Cell-Cell Recognition: Glycoproteins serve as identification tags that are specifically recognized by other cells.Selective Permeability: Control the passage of ions and molecules in and out of the cell, maintaining homeostasis. Transport Proteins: Assist in the movement of substances across the cell membrane, ensuring that essential nutrients enter the cell while waste products are expelled.
Passive and Active Membrane Transport
Passive Transport
Definition: Movement of molecules without energy expenditure, down concentration gradients (diffusion).
Types of Passive Transport:
Simple Diffusion: Direct passage of small nonpolar molecules.
Facilitated Diffusion: Utilization of transport proteins for polar/charged molecules.
Specific transmembrane proteins (channel proteins or carrier proteins) facilitate the movement of ions and polar molecules. Channel proteins form hydrophilic pores, while carrier proteins bind to solutes and undergo conformational changes.
Osmosis: Special case—passive passage of water across selectively permeable membranes.
The diffusion of water across a selectively permeable membrane from an area of higher water concentration (lower solute concentration) to an area of lower water concentration (higher solute concentration). Cells placed in hypotonic solutions swell; in hypertonic solutions, they shrink; in isotonic solutions, they remain stable.
Active Transport
Definition: Movement against concentration gradients, requiring energy (ATP).
Types of Active Transport:
Primary Active Transport: Utilizes ATP directly for transportation.
Uses ATP hydrolysis directly to pump solutes against their concentration gradient (e.g., the sodium-potassium (Na^{+}/K^{+}) pump maintains ion gradients essential for nerve impulses).
Secondary Active Transport: Relies on ion gradients created by primary transport for moving other solutes.
Also known as co-transport, it uses the electrochemical gradient established by primary active transport to move another solute. For example, the Na^{+} gradient drives glucose uptake into intestinal cells.
Endocytosis and Exocytosis
Mechanisms of Membrane Transport
Exocytosis: The process of expelling materials from the cell using vesicles that fuse with the plasma membrane.
Endocytosis: The process of engulfing materials into the cell through vesicles.
Can be divided into three types:
1. Phagocytosis (Cellular Eating): The cell engulfs large particles or whole cells by forming pseudopods, enclosing them in a large vesicle called a phagosome. Common in immune cells.
2. Bulk-phase Endocytosis (Pinocytosis - Cellular Drinking): Non-specific uptake of extracellular fluid.
3. Receptor-mediated Endocytosis: Specific binding of target molecules to receptors in coated pits, leading to uptake.
Specific molecules (ligands) bind to receptors concentrated in coated pits on the plasma membrane, triggering the formation of coated vesicles. This allows for selective uptake of specific substances in large amounts (e.g., uptake of low-density lipoproteins (LDL) into animal cells).
Signal Transduction
Pathways of Signal Reception and Response
Three Main Steps in Signal Transduction:
Reception: Signal molecule binds to specific membrane receptors.
Transduction: Conversion of the signal, often through a cascade of reactions.
The binding of a signal molecule causes a conformational change in the receptor, initiating a cascade of intracellular events, often involving relay molecules (e.g., protein kinases) and second messengers (e.g., cAMP, Ca^{2+} ions). This amplifies the signal.
Response: Cellular effects of the transduced signal, often involving changes in enzyme activity or gene expression.
The transduced signal leads to specific cellular activities, such as activating enzymes, altering gene expression in the nucleus, rearranging the cytoskeleton, or triggering cell division or apoptosis.
Role of Receptors
Types and Functions:
Receptors are integral proteins that bind specific signaling molecules in the extracellular environment.
Upon binding and activation, receptors initiate signaling cascades inside the cell.
Conclusion
Membrane structure