Physiology I - Cell Membrane and Nerve Electrophysiology

Course Introduction and Lecture Overview

• Instructor: Anna McAlinn DC, MS.
• Subject: Physiology I.
• Lecture Objectives:     * Understand the value of Physiology in the Chiropractic journey.     * Describe the cellular membrane and its role in movement of molecules into and out of the cell.     * Understand the principles of diffusion and osmosis.     * Contrast different types of membrane channels.     * List the factors that affect the net rate of diffusion.     * Explain the various mechanisms of active transport.     * Understand contributing factors to the membrane potential.     * Describe the different stages of an action potential and the indicators for each stage.     * Describe and characterize the three different types of muscle.     * Describe the structure of skeletal muscle, including major parts of the muscle fiber and their functions.

Membrane Physiology and Cell Structures

• Primary Reference: Chapter 4: Guyton and Hall, "Transport of Substances Through Cell Membranes."
• Cell Membrane Components:     * Lipid Bilayer: Composed of phospholipids.     * Phospholipid structure: Consists of Hydrophilic heads (facing extracellular and intracellular fluid) and Hydrophobic tails (facing inward).     * Chemical composition: Includes proteins and carbohydrates.     * Permeability: The membrane is selectively permeable to water and water-soluble molecules.
• Mitochondria:     * Defined as a membrane-bound organelle containing a lipid bilayer.     * Function: Serving as the site of aerobic/cellular respiration.

Mechanisms of Membrane Transport

• Diffusion (Passive Transport):     * Occurs down a concentration gradient from an area of higher concentration $[highest]$ to lower concentration $[lowest]$.     * Mechanisms: Molecules move directly through the lipid bilayer or utilize a protein "channel" or "carrier."     * Energy Requirement: No additional energy is required.
• Simple Diffusion:     * Movement occurs through membrane openings or intermolecular spaces without the use of a carrier protein.     * Lipid Soluble Substances: Oxygen, Nitrogen, Carbon Dioxide, Alcohols.
• Facilitated Diffusion:     * Substances diffuse through the membrane with the assistance of a specific carrier protein or protein channel.     * Function: Provides specificity and function to the membrane.     * Examples: Water, Ions, Glucose, and most Amino Acids (AA).     * Vmax: When a carrier is involved, transport has a maximum rate of diffusion known as $V_{max}$.
• Active Transport:     * Movement of molecules or ions against their concentration gradient (up the gradient).     * Energy Requirement: Requires energy (e.g., $ATP$).     * Involves a protein "carrier."
• Primary Active Transport:     * Uses $ATP$ directly as the energy source.     * Example: Na-K ATPase (Na+/K+ Pump):         * Active transport mechanism requiring $ATP$.         * Specific binding sites: Na-binding site and K-binding site.         * Mechanism: Transports $3Na^+$ out of the cell and $2K^+$ into the cell.         * ATPase consumes $ATP$ to facilitate this movement against gradients.
• Secondary Active Transport:     * The concentration gradient of one ion/molecule provides the energy source for the transport of another.     * Example: Na-Glucose co-transport:         * Utilizes a Glucose-binding site and a Na-binding site.         * Other examples include the transport of $Ca^{++}$ and $H^+$.

Channel Characteristics and Net Diffusion Factors

• Leak Channels:     * Characteristics: More permeable, less selective.     * Determinants: Transport is determined by the size, shape, and charge of the channel and the ions.
• Gated Channels:     * Characteristics: More selective, less permeable; they open on demand.     * Voltage-gated: Open in response to voltage changes inside the cell.     * Mechanoreceptors (Mechanically-gated): Open in response to physical deformation of the membrane.     * Chemical/Ligand-gated: Open in response to the binding of specific chemicals or ligands.
• Factors Affecting the Net Rate of Diffusion:     * Proportional to the concentration (chemical) difference across a membrane.     * Membrane electrical potential.     * Pressure difference across the membrane.
• Osmosis:     * The movement of $H_{2}O$ across a semipermeable membrane.     * Direction: Toward the area of higher solute concentration.

Membrane Potentials

• Primary Reference: Chapter 5: Guyton and Hall, "Membrane Potentials & Action Potentials."
• Contributing Factors to Membrane Potential:     * Cell permeability and ion concentration (each ion is unique).     * Permeability is affected by specific channels.     * Na+/K+ ATPase pump.     * Leak Channels.
• Electrochemical Equilibrium:     * Defined as the diffusion potential; the potential difference between the inside and outside of the cell that stops further diffusion despite the concentration gradient.     * Factors determining potential: Unequal distribution of ions and membrane permeability.
• Nernst Equation (Single Ion Potential):     * Used to calculate the equilibrium potential for a single ion: $E_{ion} (mV) = \frac{61}{z} \times \log_{10} \left( \frac{[ion]<em>{out}}{[ion]</em>{in}} \right)$.     * $z$ represents the charge of the ion.
• Goldman-Hodgkin-Katz (GHK) Equation:     * Used for real-world conditions where multiple ions must be considered.     * Considers both multiple ions and their specific membrane permeabilities.     * Formula: $V_m = 61 \log \frac{P_k [K^+]<em>{ECF} + P</em>{Na} [Na^+]<em>{ECF} + P</em>{Cl} [Cl^-]<em>{ICF}}{P_k [K^+]</em>{ICF} + P_{Na} [Na^+]<em>{ICF} + P</em>{Cl} [Cl^-]_{ECF}}$.
• Resting Membrane Potential (RMP):     * Neuronal RMP is approximately $-70\,mV$.     * Permeability dynamics: P_{K^+} > P_{Na^+} .     * K+ efflux is greater than Na+ influx, leading to a negative Intracellular Fluid (ICF).     * Maintenance: Maintained by the Na+K+ - ATPase ($3Na^+$ out, $2K^+$ in, net $-1$ charge inside) and K+ "Leak" channels (which also leak a small amount of $Na^+$).

The Action Potential

• Definition: A rapid change in voltage across the cell membrane.
• Key Characteristics: Used for long-distance communication, All-or-nothing principle, Non-decremental (strength remains constant over distance).
• Stages of an Action Potential:     1. Resting membrane potential: Baseline voltage before stimulation.     2. Depolarizing stimulus: Initial stimulus that affects the membrane.     3. Threshold: Membrane depolarizes to threshold; voltage-gated $Na^+$ and $K^+$ channels begin to open.     4. Rising Phase: Rapid $Na^+$ entry through activation gates depolarizes the cell.     5. Peak: $Na^+$ channels close (inactivation gate) and slower $K^+$ channels fully open.     6. Falling Phase: $K^+$ moves from the cell to the extracellular fluid (ECF).     7. After-hyperpolarization: $K^+$ channels remain open and additional $K^+$ leaves the cell, making the membrane potential more negative than RMP.     8. Voltage-gated K+ channels close: Less $K^+$ leaks out of the cell.     9. Return to Resting State: Cell returns to resting ion permeability and original resting membrane potential.
• Positive Feedback Loop: $Na^+$ entry creates a positive feedback loop (Rising phase triggers depolarization -> $Na^+$ channel activation gates open rapidly -> $Na^+$ enters cell -> More depolarization). The cycle stops when the slower $Na^+$ channel inactivation gate closes.

Action Potential Conduction and Refractory Periods

• Absolute Refractory Period: Prevents retrograde (backward) movement of the AP. During this time, $Na_V$ channels are inactive and $K_V$ channels are open.
• Relative Refractory Period: Follows the absolute period. $Na_V$ channels are closed (but can be reopened) and fewer $K_V$ channels remain open.
• Conduction Velocity Factors:     * Axon diameter.     * Resistance of the axon membrane to ion leakage (Myelination).
• Myelination:     * Increases conduction velocity by increasing resistance to ion leakage.     * Facilitates movement via Saltatory Conduction.
• Clinical Alterations of Electrical Activity:     * Local Anesthetics: Drugs like Lidocaine and Procaine bind to voltage-gated $Na^+$ channels to physically block action potentials.     * ECF Ion Concentrations: Changes in resting membrane potential can occur due to potassium imbalances such as Hyperkalemia or Hypokalemia.

Anatomy and Physiology of Muscle Tissue

• Primary Reference: Chapters 6, 8, & 9: Guyton and Hall.
• Skeletal Muscle:     * Control: Voluntary or Automatic.     * Appearance: Striated with long parallel cells.     * Nucleation: Multinucleated with nuclei peripherally located.     * Structure: Contains Z-disks which attach myofibrils to one another.     * Function: Contracts rapidly and vigorously but tires easily; attached to bones.
• Cardiac Muscle:     * Control: Involuntary.     * Appearance: Striated with short branched fibers.     * Nucleation: Uninucleate or binucleate.     * Structure: Intercalated disks connect cardiac cells, comprised of Desmosomes and Gap junctions.     * Function: Contracts rhythmically; timing is determined intrinsically by pacemaker tissue; found in the heart.
• Smooth Muscle:     * Control: Involuntary.     * Appearance: Striations are absent; fusiform (spindle-shaped) cells.     * Nucleation: Uninucleate.     * Types: Multi-Unit or Unitary (Unitary cells are arranged in sheets/bundles joined by gap junctions).     * Function: Contractions are slow and sustained; present in blood vessels and walls of hollow visceral organs.
• Comparative Structures (Review):     * Skeletal: Z-disks.     * Cardiac: Z-disks and Intercalated disks.     * Smooth: Dense bodies (instead of Z-disks).

Microanatomy of Skeletal Muscle

• Metabolic Demands: High energetic demands requiring high vascularization to provide $O_2$, support $ATP$ production, and remove metabolic wastes.
• Innervation:     * Efferent motor neurons: Provide input/stimulation (excitation).     * Afferent sensory neurons: Provide feedback regarding muscle length and tension.
• Terminology:     * Syncytium: Muscle fibers function as if cells are fused.     * Sarcoplasm: The cytoplasm that fills each muscle fiber.     * Myoglobin: Provides oxygen supply and gives muscle its red coloration.     * Sarcolemma: The plasma membrane of the muscle fiber.     * T-tubule: Brings action potentials into the interior of the muscle fiber.     * Sarcoplasmic Reticulum: Stores $Ca^{2+}$.     * Triad: A T-tubule flanked by two terminal cisternae.
• Myofibrils and Sarcomeres:     * Arrangement in sarcomeres provides the striated appearance and ensures cells contract in the same direction.
• Thick Filament (Myosin):     * Composed of two heavy chains and 4 light chains.     * Molecular Weight (MW): $200,000\,KD$.     * Structure: Rod-like tail terminating in two globular heads and an arm.     * Heads: Interact with actin and serve as the site of myosin ATPase.
• Thin Filament (Actin):     * Tethered to the Z-disk.     * Three components:         1. F-actin (Filamentous actin): Coiled form.         2. G-actin (Globular actin): Individual globular units.         3. Troponin: Contains three binding sites.         4. Tropomyosin: Protein that wraps around the F-actin filament.
• Other Filaments:     * Titin: An elastic fiber that keeps actin and myosin in place and allows the sarcomere to return to its original shape.     * Myomesin: Supports fiber arrangement by forming the M line.