Plasma Membranes: Structure and Function

Chapter 5: Structure and Function of Plasma Membranes

Introduction to Plasma Membranes

The plasma membrane, also known as the cell membrane, is fundamental to cellular life. Its primary basic functions are to define the cell's borders and ensure its proper functioning. It is a selectively permeable barrier, meaning it precisely controls what enters and exits the cell. Some materials can pass freely, while others require specialized structures or even energy investment to cross. Beyond merely defining boundaries, the plasma membrane also plays critical roles in:

Flexibility: Allowing cells like red and white blood cells to change shape and pass through narrow capillaries.
Cell Recognition: Bearing surface markers crucial for tissue and organ formation during early development, and later for the immune system's distinction between "self" and "non-self."
Signal Transduction: Employing complex, integral receptor proteins to transmit signals. These receptors act as both extracellular input receivers (binding effectors like hormones and growth factors) and intracellular processing activators, initiating response cascades. Notably, viruses (e.g., HIV) can hijack these receptors for cell entry, and mutations in genes encoding receptors can lead to disastrous malfunctions in signal transduction.

5.1 Components and Structure

The plasma membrane is a dynamic and highly organized structure, a concept best described by the fluid mosaic model. Its composition and arrangement are critical to its diverse functions.

The Fluid Mosaic Model

Early scientific understanding began in the 1890s with the identification of the plasma membrane, followed by its chemical components (lipids and proteins) in 1915.

Davson and Danielli (1935): Proposed the first widely accepted model, suggesting a "sandwich" structure based on its appearance in early electron micrographs. They likened proteins to the bread and lipids to the filling.
1950s Advancements: Transmission electron microscopy (TEM) revealed the membrane's core was a double rather than a single layer.
Singer and Nicolson (1972): Introduced the fluid mosaic model, which remains the best explanation for plasma membrane structure and function. This model describes the plasma membrane as a fluid combination (a mosaic) of various components, including phospholipids, cholesterol, proteins, and carbohydrates.
Thickness: Plasma membranes typically range from 5 to 10 ext{ nm} in thickness. For context, a human red blood cell is approximately 8 ext{ µm} wide, about 1,000 times wider than the membrane itself.

Principal Components of the Plasma Membrane

The plasma membrane is composed primarily of lipids (phospholipids and cholesterol), proteins, and carbohydrates.

Typical Human Cell Composition by Mass:
- Protein: Approximately 50 ext{ percent}
- Lipids (all types): Approximately 40 ext{ percent}
- Carbohydrates: Approximately 10 ext{ percent}
Variations by Cell Type: These proportions can vary significantly depending on the cell type and its function. For example, myelin, which insulates peripheral nerves, contains only 18 ext{ percent} protein and 76 ext{ percent} lipid, emphasizing its insulating role. In contrast, the mitochondrial inner membrane, crucial for cellular respiration, is 76 ext{ percent} protein and only 24 ext{ percent} lipid, reflecting its high enzymatic activity. Human red blood cell plasma membrane is approximately 30 ext{ percent} lipid.

Phospholipids

Phospholipids form the main fabric of the membrane and are amphiphilic molecules, meaning they possess both a polar (charged) and a nonpolar (uncharged) area, allowing interaction with both hydrophilic and hydrophobic environments (Figure 5.2).

Structure (Figure 5.3):
- A three-carbon glycerol backbone.
- Two fatty acid molecules attached to carbons 1 and 2. These form the hydrophobic (water-hating) tails, which are non-polar and do not form hydrogen bonds. When in water, they tend to cluster together.
- A phosphate-containing group attached to the third carbon. This forms the hydrophilic (water-loving) head, which has a polar character or a negative charge. It forms hydrogen bonds with water and other polar molecules.
Formation of Lipid Bilayer: In an aqueous environment, phospholipids spontaneously arrange themselves into a double layer (lipid bilayer). Their hydrophilic heads face outwards, interacting with the aqueous intracellular and extracellular fluids, while their hydrophobic tails face inwards, shielded from water, forming the membrane's core. This effectively separates the fluid inside the cell from the fluid outside (Figure 5.4, 5.5).
Micelles/Liposomes: When phospholipids are heated in an aqueous solution, they can spontaneously form small spheres or droplets called micelles or liposomes, with their hydrophilic heads forming the exterior and hydrophobic tails on the interior.

Proteins

Proteins are the second major component of plasma membranes, fulfilling diverse functional roles.

Integral Proteins (Integrins): As their name suggests, these proteins are integrated completely into the membrane structure. Their hydrophobic regions interact with the hydrophobic core of the phospholipid bilayer (Figure 5.2).
- Some span only a portion of the membrane, associating with a single layer.
- Others stretch across the entire membrane, exposing regions on both the interior and exterior sides. Single-pass integral membrane proteins typically have a hydrophobic transmembrane segment of 20-25 amino acids. More complex proteins can have up to 12 such segments, extensively folded (Figure 5.5).
- They typically have hydrophilic regions that protrude into the aqueous cytosol or extracellular fluid and mildly hydrophobic regions adjacent to the phospholipid tails.
- Functions include transport, signal reception (receptors), and enzymatic activity.
Peripheral Proteins: These proteins are located on the membrane's exterior or interior surfaces, attached to either integral proteins or directly to phospholipids. They are not embedded within the bilayer itself.
- Functions include serving as enzymes, providing structural attachments for cytoskeleton fibers, or acting as cell recognition sites (often called "cell-specific" proteins). The body's immune system distinguishes its own proteins from foreign ones, like those associated with pathogens.

Carbohydrates

Carbohydrates are the third major component, always found on the cell's exterior surface. They are attached to proteins, forming glycoproteins, or to lipids, forming glycolipids (Figure 5.2).

Structure: These carbohydrate chains can consist of 2-60 monosaccharide units and can be either straight or branched.
Functions:
- Cell Recognition: Along with peripheral proteins, carbohydrates form specialized, unique patterns on the cell surface that allow cells to recognize each other. This is crucial for immune response (distinguishing "self" from "non-self"), embryonic development (tissue and organ formation), and cell-to-cell attachments.
- Glycocalyx ("Sugar Coating"): The collective name for these exterior carbohydrates. The glycocalyx is highly hydrophilic, attracting significant amounts of water to the cell surface, which aids in cell interaction with its watery environment and uptake of dissolved substances.

Evolution Connection: How Viruses Infect Specific Organs

The unique glycoprotein and glycolipid patterns on cell surfaces are exploited by many viruses for infection. For instance, HIV and hepatitis viruses exhibit organ- or cell-specific infections:

HIV: Penetrates the plasma membranes of T-helper cells (a type of lymphocyte), monocytes, and central nervous system cells.
Hepatitis Virus: Attacks liver cells.

This specificity arises because these target cells possess binding sites on their surfaces that are compatible with specific viral proteins (Figure 5.6). Viral surface recognition sites also interact with the human immune system, prompting antibody production.

Immune Evasion: Unfortunately, HIV's recognition sites change rapidly due to frequent mutations, making it extremely challenging to develop an effective vaccine. This rapid evolution allows the virus to adapt, creating variants that evade the immune system's antibodies. Compounding this, HIV specifically infects and destroys immune cells, further compromising the host's defense.

Membrane Fluidity

The "mosaic" aspect of the fluid mosaic model highlights that integral proteins and lipids are separate but loosely attached molecules that can move somewhat relative to one another. However, the membrane is not a balloon; it is relatively rigid and can burst if penetrated or if a cell takes in too much water. Nevertheless, its mosaic nature allows a fine needle to penetrate and the membrane to self-seal upon withdrawal.

Several factors contribute to and maintain this fluid characteristic:

Nature of Phospholipids:
- Saturated Fatty Acid Tails: These tails are straight, with no double bonds between carbon atoms. At colder temperatures, they can pack tightly, making the membrane dense and rigid.
- Unsaturated Fatty Acid Tails: These tails contain double bonds, which cause a "kink" or bend of approximately 30 degrees (Figure 5.3). These kinks prevent tight packing of adjacent phospholipid molecules, creating "elbow room" that helps maintain fluidity even at lower temperatures, preventing the membrane from solidifying. Many organisms, such as fish, adapt to cold environments by increasing the proportion of unsaturated fatty acids in their membranes.
Cholesterol (in Animals): Cholesterol molecules are situated alongside phospholipids and act as a buffer against temperature extremes.
- At lower temperatures, cholesterol prevents phospholipids from packing too closely, thereby maintaining fluidity.
- At higher temperatures, it restricts phospholipid movement, preventing the membrane from becoming too fluid.
- This dual action extends the functional temperature range for the membrane. Cholesterol also helps organize clusters of transmembrane proteins into specialized regions called lipid rafts.

Summary of Plasma Membrane Components and Functions (Table 5.1):

Phospholipid: Main membrane fabric.
Cholesterol: Attached between phospholipids and between the two phospholipid layers; maintains fluidity; organizes lipid rafts.
Integral proteins: Embedded within the phospholipid layer(s) (may span both layers); transport, receptors, enzymes, structural attachments, recognition.
Peripheral proteins: On the phospholipid bilayer's inner or outer surface (not embedded); enzymes, structural attachments, recognition sites.
Carbohydrates: Generally attached to proteins (glycoproteins) or lipids (glycolipids) on the outside membrane layer; cell identification, self/non-self distinction, cell-to-cell attachment.

Career Connection: Immunologist

Immunologists are physicians and scientists who specialize in the study of the immune system. They investigate the variations in peripheral proteins and carbohydrates that serve as cell recognition sites, which are central to immune function.

Key Roles:
- Research and develop vaccines for infectious diseases (e.g., smallpox, polio, diphtheria, tetanus).
- Treat and study allergies.
- Investigate and treat autoimmune diseases (where the immune system attacks a person's own cells, e.g., lupus).
- Address immunodeficiencies, both acquired (e.g., AIDS) and hereditary (e.g., severe combined immunodeficiency, SCID).
- Manage organ transplantation patients by suppressing their immune systems to prevent organ rejection.
- Explore natural immunity, environmental impacts on the immune system, and the immune system's role in diseases like cancer (a historically underappreciated area).
Qualifications: To become an immunologist, one typically needs a PhD or MD, followed by at least 2-3 years of training in an accredited program and passing the American Board of Allergy and Immunology exam.
Required Knowledge: Deep understanding of human body function, pharmacology, and medical technology (medications, therapies, test materials, surgical procedures).

5.2 Passive Transport

Plasma membranes are selectively permeable, meaning they allow specific substances to pass through while restricting others. This selectivity is vital for cell survival. Passive transport is a natural phenomenon where substances move across the membrane without the cell expending any energy.

Basics of Passive Transport

Substances move down a concentration gradient, from an area of higher concentration to an area of lower concentration, until concentrations are equal across the space.
A concentration gradient is a range of concentrations for a single substance across a physical space.

Selective Permeability and Substance Movement

The plasma membrane's asymmetric nature (interior not identical to exterior) and amphiphilic properties (hydrophilic regions facing water, hydrophobic core) contribute to its selective permeability (Figure 5.7).

Easily Permeable Substances:
- Non-polar, lipid-soluble materials with low molecular weight: These can easily slip through the membrane's hydrophobic lipid core. Examples include fat-soluble vitamins (A, D, E, K), fat-soluble drugs, hormones, oxygen ( ext{O}2) and carbon dioxide ( ext{CO}2) (which have no charge).
Challenging Substances:
- Polar substances: While they might connect with the cell's exterior, they struggle to pass through the lipid core.
- Small ions: Despite their small size, their charge prevents them from easily passing through the membrane's mosaic. Ions like sodium ( ext{Na}^+), potassium ( ext{K}^+), calcium ( ext{Ca}^{2+}), and chloride ( ext{Cl}^-$) require special transport mechanisms.
- Simple sugars and amino acids: Also need the help of various transmembrane proteins (channels or carriers) to cross plasma membranes.

Diffusion

Diffusion is a passive transport process where a single substance moves from a high-concentration area to a low-concentration area until the concentration is uniform across an entire space.

Mechanism: Molecules move constantly and randomly. If a concentration gradient exists, there will be a net movement from high to low concentration. For example, ammonia gas released in a room will spread from its highest concentration point (the bottle) to the edges of the room until evenly distributed (Figure 5.8).
Energy: Diffusion expends no cellular energy. The concentration gradient itself represents a form of potential energy that dissipates as the gradient is eliminated.
Independence: Each substance in a medium (e.g., extracellular fluid) diffuses according to its own concentration gradient, independently of other materials.
Dynamic Equilibrium: Once a substance has completely diffused and its concentration gradient is removed, there is no net movement of molecules from one area to another, even though individual molecules continue to move randomly.

Factors Affecting the Rate of Diffusion

Several factors influence how rapidly a substance diffuses:

Extent of the Concentration Gradient: A greater difference in concentration leads to more rapid diffusion. As the material's distribution approaches equilibrium, the diffusion rate slows.
Mass of the Molecules Diffusing: Lighter molecules move and diffuse more quickly than heavier ones.
Temperature: Higher temperatures increase the kinetic energy and movement of molecules, thereby increasing the diffusion rate. Conversely, lower temperatures decrease energy and diffusion rates.
Solvent Density: Increased solvent density decreases the diffusion rate because molecules have more difficulty moving through a denser medium. Conversely, a less dense medium increases diffusion. In living cells, dehydration increases cytoplasm density, impairing diffusion (e.g., in neurons, potentially leading to unconsciousness or coma).
Solubility: Nonpolar or lipid-soluble materials pass through plasma membranes more easily than polar materials, resulting in a faster diffusion rate.
Surface Area and Plasma Membrane Thickness: An increased surface area enhances the diffusion rate, while a thicker membrane reduces it.
Distance Travelled: The greater the distance a substance must travel, the slower the diffusion rate. This factor places an upper limit on cell size; large spherical cells cannot efficiently transport nutrients to and wastes from their centers, necessitating small or flattened cell morphologies.

Filtration (a Variation of Diffusion)

Filtration involves the movement of material through a membrane according to its concentration gradient, frequently enhanced by pressure.

Mechanism: Pressure can accelerate the diffusion rate, causing substances to filter more rapidly.
Example: In the kidneys, blood pressure forces large quantities of water and dissolved solutes out of the blood and into the renal tubules. The diffusion rate here is predominantly pressure-dependent. Abnormally high blood pressure can even force proteins into the urine, which is usually not observed.

Facilitated Transport (Facilitated Diffusion)

In facilitated transport, materials diffuse across the plasma membrane with the assistance of integral membrane proteins. Although it uses proteins, it is still a passive process as it involves movement down a concentration gradient and does not require cellular energy.

Need for Facilitation: This mechanism is essential for polar molecules and ions, which are repelled by the hydrophobic core of the cell membrane, preventing their free diffusion.
Process: Transport proteins shield these materials from the membrane's repulsive forces.
- The transported material first attaches to protein or glycoprotein receptors on the plasma membrane's exterior surface.
- Then, the substance passes to specific integral proteins (channels or carriers) that facilitate its movement.

Types of Transport Proteins for Facilitated Diffusion

Transport proteins are transmembrane proteins specific to the substance they transport and function as either channels or carriers.

Channels (Figure 5.9):
- These are integral proteins that form a hollow, hydrated channel through their core, enabling polar compounds to bypass the membrane's nonpolar central layer.
- Channels are specific for the transported substance and have hydrophilic domains exposed to both intracellular and extracellular fluids.
- Aquaporins are specialized channel proteins that allow water to pass through membranes at a very high rate.
- Gated vs. Open: Some channel proteins are always open, allowing free passage (e.g., some ext{Na}^+ and ext{Cl}^- channels in certain tissues). Others are "gated," meaning their opening is controlled by the attachment of specific ions, other substances, or specific mechanisms. Gated channels in nerve and muscle cells for ext{Na}^+, ext{K}^+, and ext{Ca}^{2+} are crucial for electrical impulse transmission and muscle contraction.
- Transport Rate: Channels facilitate diffusion at an extremely high rate, moving tens of millions of molecules per second.
Carrier Proteins (Figure 5.10):
- These integral proteins bind to a specific substance, triggering a change in their own shape, which then moves the bound molecule across the membrane.
- Movement can occur in either direction, depending on the concentration gradient.
- Specificity and Saturation: Carrier proteins are typically specific for a single substance. There is a finite number of these proteins in membranes; once all are bound to their ligands, they become saturated, and the transport rate reaches its maximum. Increasing the concentration gradient further will not increase the transport rate.
- Example: In the kidney, glucose is filtered and reabsorbed via carrier proteins. If blood glucose levels are too high (e.g., in diabetes), the carrier proteins become saturated, and excess glucose is not reabsorbed, leading to "spilling glucose into the urine." Glucose transport proteins (GLUTs) are a family of carrier proteins involved in transporting glucose and other hexose sugars.
- Transport Rate: Carrier proteins operate at a slower rate than channels, moving thousands to a million molecules per second.

Osmosis

Osmosis is the specialized transport of water across a semipermeable membrane. It occurs according to water's concentration gradient, which is inversely proportional to the concentration of solutes that cannot pass through the membrane.

Mechanism (Figure 5.11): Water moves from an area of higher water concentration (lower solute concentration) to an area of lower water concentration (higher solute concentration). For example, if two solutions separated by a semipermeable membrane have different solute concentrations, water will move from the side with a higher proportion of water molecules (less solute) to the side with a lower proportion of water molecules (more solute). This diffusion of water continues until the water's concentration gradient is eliminated or until the osmotic pressure (pressure required to stop osmosis) is balanced by hydrostatic pressure.
Role of Aquaporins: Aquaporins, specialized channel proteins for water, play a significant role in facilitating the high rate of water movement in osmosis, particularly in red blood cells and kidney tubules.
Living Systems: Osmosis is a constant process fundamental to maintaining fluid balance in living organisms.

Tonicity

Tonicity describes how an extracellular solution can affect a cell's volume by influencing osmosis. It directly correlates with the solution's osmolarity, which is the total solute concentration.

Low Osmolarity: Indicates a greater number of water molecules relative to solute particles.
High Osmolarity: Indicates fewer water molecules relative to solute particles.
In a system where a membrane is permeable to water but not solute, water will move from the side of lower osmolarity (more water) to the side of higher osmolarity (less water) along its concentration gradient.

Types of Solutions in Relation to Cell Cytoplasm (Figure 5.12)

Hypotonic Solutions:
- The extracellular fluid has a lower osmolarity (lower solute concentration, higher water concentration) than the fluid inside the cell (i.e., the cytoplasm).
- Water follows its concentration gradient and enters the cell.
- Effect on Cells: Cells swell.
Hypertonic Solutions:
- The extracellular fluid has a higher osmolarity (higher solute concentration, lower water concentration) than the cell's cytoplasm.
- The cell has a relatively higher water concentration than its external environment.
- Water leaves the cell.
- Effect on Cells: Cells shrink.
Isotonic Solutions:
- The extracellular fluid has the same osmolarity as the cell's cytoplasm.
- There is no net movement of water into or out of the cell, though water molecules still move in and out equally.
- Effect on Cells: No change in cell size.

Visual Connection Question: If a doctor injects a patient with what is thought to be an isotonic saline solution, but the patient dies and an autopsy reveals destroyed red blood cells, this indicates the solution was not isotonic. Instead, it was likely hypotonic, causing water to rush into the red blood cells, making them swell and burst (lyse).

Tonicity in Living Systems

Maintaining appropriate tonicity is crucial for cell function and survival. Extreme hypotonic or hypertonic conditions can compromise and destroy cells.

Hypotonic Environments:
- Red Blood Cells: Will continue to swell as water enters until they burst, or lyse, if the plasma membrane can no longer expand (due to discrete spaces between molecules becoming too large).
- Plant Cells ( Figure 5.13): Surrounded by rigid cell walls, they are protected from lysis. Water inflow creates turgor pressure, which stiffens the cell walls and supports the plant. Plant cytoplasm is typically slightly hypertonic to its environment, so water is constantly drawn in, maintaining turgor.
- Osmoregulation: Organisms have developed mechanisms to control osmosis. For example:
  - Protists (e.g., Paramecium, Amoeba): Lack cell walls and possess contractile vacuoles that actively pump excess water out of the cell to prevent lysis in hypotonic freshwater environments (Figure 5.15).
  - Marine Invertebrates: Often have internal salt levels matched to their environment, making them isotonic with seawater.
  - Freshwater Fish: Live in a hypotonic environment (cells are hypertonic). They actively absorb salt through their gills and excrete large volumes of dilute urine.
  - Saltwater Fish: Live in a hypertonic environment (cells are hypotonic). They actively secrete salt through their gills and excrete highly concentrated urine.
  - Vertebrates: Kidneys regulate body water, and osmoreceptors in the brain monitor blood solute concentration, triggering hormone release to adjust water loss.
  - Albumin: High concentrations of this protein (produced by the liver) in vertebrate blood are too large to pass through membranes easily and help control osmotic pressures in tissues.
Hypertonic Environments:
- Red Blood Cells: Water leaves the cell, causing it to shrink or crenate. This concentrates the intracellular solutes, making the cytosol denser, interfering with diffusion, and compromising cell function, potentially leading to cell death.
- Plant Cells (Figure 5.14): If a plant cell is in a hypertonic solution (e.g., when a plant is not watered), water leaves the cell. The cell wall prevents overall shrinkage, but the cell membrane detaches from the wall, and the cytoplasm constricts—a process called plasmolysis. The plant loses turgor pressure and wilts.

5.3 Active Transport

Active transport mechanisms move substances across the plasma membrane, but unlike passive transport, they require the cell to expend energy, typically in the form of adenosine triphosphate (ATP). This is necessary when substances must be moved against their concentration gradient (from an area of lower concentration to an area of higher concentration).

Electrochemical Gradient

In living systems, gradients are more complex than simple concentration gradients for uncharged substances. For ions, both a concentration gradient and an electrical gradient combine to determine their movement:

Electrical Gradient: Living cells maintain a difference in charge across their plasma membrane, with the interior being electrically negative relative to the extracellular fluid. This occurs because ions move in and out, and the cell contains large, mostly negatively charged proteins that do not cross the membrane.
Combined Force: The combination of an ion's concentration gradient and the electrical charge difference across the membrane is called its electrochemical gradient (Figure 5.16).
- Sodium ($ ext{Na}^+$): Both its concentration gradient (higher outside) and electrical gradient (attraction to negative interior) drive ext{Na}^+ into the cell.
- Potassium ($ ext{K}^+$): The electrical gradient drives ext{K}^+ into the cell (positive ion attracted to negative interior), but its concentration gradient (higher inside) drives ext{K}^+ out of the cell.

Visual Connection Question: Injecting a potassium solution into a person's blood is lethal because it drastically alters the electrochemical gradient for ext{K}^+. Cells maintain a high internal ext{K}^+ concentration. A sudden increase in external ext{K}^+ would reduce or even reverse the normal outward concentration gradient, causing ext{K}^+ to rush into cells or prevent its efflux. This uncontrolled ion movement disrupts the electrical activity critical for nerve impulse transmission and muscle contraction (especially in the heart), leading to cardiac arrest.

Moving Against a Gradient

To move substances against their electrochemical gradient, cells must continuously expend energy, primarily from ATP generated through cellular metabolism. Active transport mechanisms, often called pumps, maintain the necessary concentrations of ions and other substances despite constant passive movements. For instance, red blood cells devote most of their metabolic energy to maintaining ext{Na}^+ and ext{K}^+ imbalances. Active transport is sensitive to metabolic poisons because these interfere with ATP supply.

Two main mechanisms exist for active transport of small molecules and ions:

Primary Active Transport: Directly utilizes ATP hydrolysis to move substances across the membrane and can create a difference in charge across the membrane.
Secondary Active Transport: Does not directly consume ATP but instead uses the energy stored in the electrochemical gradient established by primary active transport.

Carrier Proteins for Active Transport (Transporters/Pumps)

Specific carrier proteins, or pumps, are essential for active transport. There are three types of these transporters (Figure 5.17):

Uniporter: Carries one specific ion or molecule in one direction.
Symporter: Carries two different ions or molecules simultaneously in the same direction.
Antiporter: Carries two different ions or molecules simultaneously in opposite directions.

These transporters can also move small, uncharged organic molecules like glucose. While similar protein types exist in facilitated diffusion, in active transport, they explicitly require energy.

Examples of Active Transport Pumps:
- ext{Na}^+ - ext{K}^+ ATPase (antiporter): Transports sodium and potassium ions.
- ext{H}^+ - ext{K}^+ ATPase (antiporter): Transports hydrogen and potassium ions.
- ext{Ca}^{2+} ATPase (uniporter): Transports calcium ions.
- ext{H}^+ ATPase (uniporter): Transports hydrogen ions.

Primary Active Transport

Primary active transport directly consumes ATP to drive the movement of specific ions, creating an electrochemical gradient (electrogenic transport) (Figure 5.18).

The Sodium-Potassium Pump ($ ext{Na}^+ - ext{K}^+ ATPase): This is arguably the most crucial pump in animal cells, maintaining the electrochemical gradient and regulating ext{Na}^+ and ext{K}^+ concentrations.
- Mechanism (Six Steps):
  1. The carrier protein faces the cell's interior and has a high affinity for ext{Na}^+. Three ext{Na}^+ ions bind to it.
  2. The protein hydrolyzes ATP, and a low-energy phosphate group attaches to the carrier.
  3. The carrier protein changes shape and reorients towards the membrane's exterior. Its affinity for ext{Na}^+ decreases, and the three ext{Na}^+ ions are released outside the cell.
  4. The shape change increases the carrier's affinity for ext{K}^+. Two ext{K}^+ ions bind to the protein, and the attached phosphate group detaches.
  5. With the phosphate group removed and ext{K}^+ bound, the carrier protein repositions itself towards the cell's interior.
  6. In this new configuration, the carrier's affinity for ext{K}^+ decreases, and the two ext{K}^+ ions are released into the cytoplasm. The protein's affinity for ext{Na}^+ increases, and the cycle restarts.
- Net Result: For every three ext{Na}^+ ions pumped out of the cell, two ext{K}^+ ions are pumped into the cell. This unequal exchange of positive charges results in the cell's interior becoming slightly more negative relative to the exterior, making the sodium-potassium pump an electrogenic pump that contributes significantly to the membrane potential.

Secondary Active Transport (Co-transport)

Secondary active transport leverages the electrochemical gradient established by primary active transport to move other substances against their own concentration gradients. It does not directly use ATP.

Mechanism (Figure 5.19): Primary active transport, like the sodium-potassium pump, creates a high concentration of ext{Na}^+ outside the cell. When a channel protein opens, ext{Na}^+ ions rush back into the cell down their electrochemical gradient. This downhill movement of ext{Na}^+ provides the energy to co-transport other substances (e.g., amino acids, glucose, lactose) against their gradients.
Examples: Many amino acids and glucose enter cells this way.
Mitochondrial ATP Production: This principle is also used in the mitochondria of plant and animal cells, where the potential energy accumulated in stored hydrogen ions is converted to kinetic energy as they flow through ATP synthase, driving ATP synthesis from ADP.

Visual Connection Question: If the pH outside the cell decreases (meaning an increased concentration of hydrogen ions, ext{H}^+), and if the transport of amino acids into the cell occurs via a symporter that couples with ext{H}^+ (co-transporting ext{H}^+ down its gradient with amino acids), then a decreased extracellular pH would likely increase the amount of amino acids transported into the cell. The larger ext{H}^+ gradient would provide a stronger driving force for the symporter.

5.4 Bulk Transport

Beyond small ions and molecules, cells also need to transport larger molecules, entire cellular components, and even whole unicellular organisms. This process, known as bulk transport, requires significant energy expenditure (ATP).

Endocytosis

Endocytosis is an active transport mechanism that moves particles, such as large molecules (macromolecules), parts of cells, and even whole cells, into a cell.

Common Characteristic: The plasma membrane invaginates, forming a pocket around the target particle. This pocket then pinches off, creating a newly formed intracellular vesicle containing the particle, derived from the plasma membrane.

Variations of Endocytosis

Phagocytosis ("Cell Eating") (Figure 5.20):
- This process involves the cell taking in large particles, such as other cells or significant cellular debris. For example, neutrophils (a type of white blood cell) engulf and destroy invading microorganisms.
- Mechanism:
  - A portion of the plasma membrane's inward-facing surface is coated with the protein clathrin, stabilizing that section.
  - The coated membrane extends and surrounds the particle, eventually enclosing it within a vesicle.
  - Once inside the cell, clathrin disengages.
  - The vesicle merges with a lysosome, where digestive enzymes break down the contents in the newly formed compartment (endosome).
  - After accessible nutrients are extracted, the endosome fuses with the plasma membrane, releasing any waste products into the extracellular fluid. The endosomal membrane then reintegrates into the plasma membrane.
Pinocytosis ("Cell Drinking") (Figure 5.21):
- Discovered by Warren Lewis in 1929, this process involves the cell taking in small volumes of extracellular fluid and the molecules dissolved within it.
- It results in much smaller vesicles than phagocytosis and generally does not require merging with a lysosome.
- Potocytosis (a variation): Uses a different coating protein, caveolin, on the cytoplasmic side of the plasma membrane. It forms small vacuoles within caveolae (invaginations rich in membrane receptors and lipid rafts). Potocytosis brings small molecules into the cell and can transport them through the cell to the other side, a process called transcytosis.
Receptor-Mediated Endocytosis (Figure 5.22):
- A highly targeted form of endocytosis that utilizes specific receptor proteins embedded in the plasma membrane. These receptors have a high binding affinity for particular substances.
- Similar to phagocytosis, clathrin attaches to the cytoplasmic side of the plasma membrane, coating the pits where receptors bind their specific ligands.
- Clinical Significance: This process is crucial for removing specific substances from tissue fluids or blood. Its ineffectiveness causes certain human diseases. For instance, in familial hypercholesterolemia, defective or missing LDL (low-density lipoprotein, or "bad" cholesterol) receptors prevent the removal of LDL particles from the blood, leading to life-threatening high cholesterol levels.
- Viral Exploitation: Many viruses (e.g., flu viruses) and toxins (e.g., diphtheria, cholera) exploit this pathway by having sites that cross-react with normal receptor-binding sites, gaining entry into cells.

Exocytosis

Exocytosis is the reverse of endocytosis; it is the process by which cells move bulk material out of the cell into the extracellular fluid.

Mechanism (Figure 5.23): Waste materials, secreted proteins, or neurotransmitters are packaged into membrane-bound vesicles within the cell. These vesicles then migrate to the plasma membrane, fuse with its interior surface, and open, releasing their contents into the extracellular space.
Examples: Secretion of extracellular matrix proteins and the release of neurotransmitters into the synaptic cleft by synaptic vesicles are key examples of exocytosis.

Summary of Transport Methods, Energy Requirements, and Materials Transported (Table 5.2):

Diffusion: Passive; Small-molecular weight material.
Osmosis: Passive; Water.
Facilitated Transport/Diffusion: Passive; Sodium, potassium, calcium, glucose.
Primary Active Transport: Active; Sodium, potassium, calcium.
Secondary Active Transport: Active; Amino acids, lactose.
Phagocytosis: Active; Large macromolecules, whole cells, or cellular structures.
Pinocytosis and Potocytosis: Active; Small molecules (liquids/water).
Receptor-Mediated Endocytosis: Active; Large quantities of macromolecules.