Physiology Notes

Contents

1. Introduction
   • Homeostasis
   • Cell Physiology
   • Proteins
2. Cell Transport
   • Diffusion (and Ion Trapping)
   • Facilitated Diffusion
   • Active Transport
3. Osmosis and Tonicity
   • Osmosis
   • Tonicity
   • Filtration and Absorption
4. Endocrine System
5. Nervous System
   • Neurons
   • Membrane Potential
   • Action Potential

Introduction

Lumen are cavities that extend into the body.

There are four main fluid compartments:

1. Intracellular fluid inside of cells
2. Interstitial fluid outside of cells and blood vessels
3. Plasma inside of blood vessels
4. Glycocalyx

Homeostasis

Homeostasis is the ability to keep the internal environment within a tolerable range.

Feedback systems maintain homeostasis. In a positive feedback system, stimuli is received by the receptor, which sends the information to the integrating center, which sends instructions to the effector, which carries out the response. For example, a drop in blood pressure causes the heart to speed up and the kidneys to retain fluid.

Cell Physiology

Mitochondria converts sugar, fats, proteins, and O2 into ATP and CO2 through cellular respiration.

The cell membrane is a protein-studded phospholipid bilayer. The head of the phospholipid is polar (hydrophilic) and the fatty tails are nonpolar (hydrophobic).

The membrane is selectively permeable, allowing some substances to pass while blocking others. Small, nonpolar molecules (O2, CO2, ethanol) can pass through easily. Large polar molecules (glucose) and ions (Na+, K+) require assistance.

Oxygen and nitrogen are highly electronegative, causing them to pull electrons toward themselves in a covalent bond. This creates a polar molecule with partial positive and negative charges.

Proteins

Amino acids can link together to form:

• Peptides (2-9 amino acids)
• Polypeptides (10-100 amino acids)
• Proteins (>100 amino acids)

The structure of proteins can be described in four levels:

1. 1st structure is the sequence of amino acids
2. 2nd structure is folding into α-helixes and β-pleated sheets
3. 3rd structure is the overall fibrous or globular shape
4. 4th structure is the combination of multiple proteins

There are four forces that fold a polypeptide chain:

1. Hydrogen bonds form between polar groups
2. van der Waals forces form from temporary dipoles
3. Ionic bonds form between charged groups
4. Covalent bonds form from sharing electrons

Hemoglobin is dull red when deoxygenated and bright red when oxygenated. This is an example of how conformational changes in proteins can affect their function.

Cell Transport

Molecules can get across the membrane in four ways:

1. Diffusion
2. Facilitated diffusion (ion channels, carrier proteins)
3. Active transport (primary, secondary, vesicular)

Diffusion

The rate of diffusion, or flux, is affected by

• Solubility of molecule ($S$)
• Surface Area ($A$)
• Concentration gradient ($C_0 - C_1$)
• Size of molecule ($M$)
• Distance ($d$)
• Temperature

This is given by the equation:

Sometimes the solubility, size of the molecule, and distance are combined into a permeability coefficient ($P$):

Permeability is affected by several factors:

1. Non-polar molecules are more permeable than polar molecules
2. Weak acids are permeable when protonated $$A^- + H^+ \rightleftharpoons HA$$
3. Weak bases are permeable when unprotonated $$A + H^+ \rightleftharpoons HA^+$$

Ion Trapping

Suppose there is a pH gradient across the membrane. Then more weak acids will protonated into $HA$ on the side that has a higher concentration of $H^+$. This will increase diffusion of $HA$ across the membrane. Once inside the cell, the weak acid will dissociate again, trapping it inside.

Note that $\text{pH} = -\log[H^+]$. That means that a lower pH corresponds to a higher concentration of $H^+$ ions.

Drugs are usually weak acids or weak bases, so they can take advantage of ion trapping. Pharmaceutical companies designing drugs must take into account that the pH of the stomach is between 1-2, and the pH of the small intestine is between 6-7.

Facilitated Diffusion

Facilitated diffusion can happen through ion channels and carrier proteins.

Ion channels have three properties: selectivity, permeability, and gating. Outside of the cell, each ion is surrounded by water molecules (sphere of hydration), which gives the ion some geometry. The aqueous pore of the ion channel has the same geometry as the sphere of hydration, allowing the ion to pass through.

Carrier proteins have three properties: specificity, saturability and competition. Saturability and competition arise because there are a limited number of carrier proteins and potentially multiple types of molecules that can bind to them.

Active Transport

Primary active transport uses ATP to move molecules against their concentration gradient. An example is the sodium-potassium pump, which moves 3 Na+ ions out of the cell and 2 K+ ions into the cell for each ATP hydrolyzed.

Secondary active transport uses the energy from one molecule moving down its concentration gradient to move another molecule against its concentration gradient. This can be done via cotransport (same direction) or countertransport (opposite direction).

Vesicular transport uses vesicles to move large molecules across the membrane. Endocytosis brings molecules into the cell, while exocytosis sends molecules out of the cell.

Osmosis and Tonicity

Osmosis

Osmosis is the diffusion of water across a selectively permeable membrane (through aquaporin channels).

Osmotic pressure ($\pi$) is a measure of how strongly water wants to move into a solution. If one side of the membrane has more solute particles (and higher osmotic pressure), then water will move toward that side.

The equation for osmotic pressure is given by:

Where:

1. $C$ is the concentration of solute particles in mOsm/L
2. $T$ is the temperature in K
3. $R$ is the gas constant in atm/mol · K

Note that mOsm is the number of particles a substance dissolves into in the solution. For example, NaCl dissolves into Na+ and Cl-, so 1 mole of NaCl produces 2 Osm.

Tonicity

Tonicity is a measure of how a solution affects cell volume.

1. Hypertonic solutions cause cells to shrink
2. Isotonic solutions cause no change in cell volume
3. Hypotonic solutions cause cells to swell

For human cells, an isotonic solution is generally 300 mOsm/L.

Note that tonicity is only affected by the concentration of non-penetrating solutes. There is also a measure called osmolarity that depends on the total concentration of solutes (both penetrating and non-penetrating).

Filtration and Absorption

Fluid moves from the capillaries into the interstitial fluid (filtration), and from the interstitial fluid back into the capillaries (absorption). To do this, it must pass through the endothelial cells that line the capillaries. This can happen through diffusion, bulk flow, or vesicular transport.

Fluid exchange between capillaries (plasma) and interstitial fluid is governed by Starling forces:

1. Hydrostatic pressure caused by the pumping action of the heart pushes fluid out of the capillaries. This pressure decreases along the length of the capillary.
2. Colloid osmotic pressure from the proteins within the capillary pulls fluid into the capillaries. It remains relatively constant along the length of the capillary.

This is why filtration generally occurs at the arterial end of the capillary (higher hydrostatic pressure) and absorption occurs at the venous end of the capillary (lower hydrostatic pressure).

Starling forces also explains why elevating an injured limb helps reduce swelling. It decreases hydrostatic pressure, reducing fluid leakage into the interstitial space.

Recently, the glycocalyx layer lining the endothelial cells has been found to play an important role in fluid exchange. It acts as a barrier to protein movement, modulating colloid osmotic pressure across the capilary. This promotes more filtration and less absorption.

Endocrine System

The hypothalamus produces releasing factors that stimulate the anterior pituitary gland. The anterior pituitary gland then releases hormones through the bloodstream. These hormones can have direct effects on target tissues or stimulate other endocrine glands to release hormones.

For example, the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH). TSH then stimulates the thyroid gland to release thyroid hormones (T3 and T4) in the bloodstream. T3 and T4 are lipid-soluble hormones that enter cells and bind to nuclear receptors, affecting gene transcription.

Question: How do you store something that is lipid-soluble?

T3 and T4 are covalently bonded together in a non-penentrating protein called thyroglobulin and stored in the colloid of the thyroid gland. When T3 and T4 are needed, the cell endsocytoses the thyroglobulin, breaks the covalent bond, and releases T3 and T4 into the bloodstream.

Question: What is determining the volume of the thyroid gland?

Most of the volume of the thyroid gland comes from the colloid. When the colloid swells up, the thyroid gland swells up and becomes a goiter. The colloid swells up when there is high osmotic pressure (caused by a high concentration of thyroglobulin).

Nervous System

Neurons

Neurons are very large cells with high metabolic demands. As soon as resources are cut off, they immediately start to malfunction. Long projecting neurons are the first to show signs of disease, which manifests as tingling or numbness in hands in feet.

Astrocytes line the capillaries and tightly regulate what can come out of it (blood-brain barrier).

Afferent neurons receive signals from sensory receptors. Interneurons in the central nervous system connect the afferent neurons to the efferent neurons. The efferent neuron sends signals to muscles, glands, and other tissue through the axon terminal.

1. Dendrites receive inputs from other cells
2. Soma (cell body) integrates all input
3. Axon hillock decides whether to fire an action potential
4. Axon conducts the action potential down the length of the neuron
5. Presynaptic axon terminals release chemical signalling molecules

Membrane Potential

All cells exhibit a membrane potential (Vm) across the membrane. The inside of the cell is typically negative relative to the outside. The potential energy can be used to do work. Excitable cells (neurons, muscles) use changes in membrane potential to send signals.

Cells use energy (ATP) to create a chemical gradient with K+ and Na+. K+ has a higher concentration inside the cell, while Na+ has a higher concentration outside the cell.*

If more K+ channels are opened, then more K+ will leave the cell, making the inside more negative. If more Na+ channels are opened, then more Na+ will enter the cell, making the inside more positive. Ion channels will not appreciably change the concentration of K+ and Na+.

*Note that 3 Na+ are pumped out of the cell and 2 K+ are pumped into the cell for each ATP hydrolyzed, so there is also a small membrane potential from that.

To reach electrochemical equilibrium, the chemical gradient must be balanced by the electrical gradient. Relatively few ions need to move to create a significant electrical gradient. This is described by the Nernst equation:

Where:

1. $R$ is the gas constant
2. $T$ is the temperature
3. $z$ is the ion charge
4. $F$ is Faraday's constant

If there are multiple permeable ions, then the membrane potential is given by the Goldman-Hodgkin-Katz equation:

Where:

• $P_{\text{ion}}$ is the permeability of the ion, which is impacted by number of ion channels
• $[\text{ion}]$ is the concentration of the ion

From Ohm's Law, we can derive this equation for current:

Where:

1. $I$ is current
2. $g$ is the membrane conductance
3. $V_m$ is the membrane potential
4. $E_{\text{ion}}$ is the equilibrium potential

Note that:

• When $I$ is positive, there is an outward current (positive charge exiting the cell or negative charge entering the cell).
• $E_{\text{ion}}$ is maintained at a constant level.
• $V_m$ changes rapidly.
• $g$ has some components that are constant (leak channels) and some components that change rapidly (gated channels). $g$ can change rapidly.
• Driving force $V$ is the difference between the membrane potential $V_m$ and the equilibrium potential $E_{\text{ion}}$.

If the number of open ion channels changes, then the conductance $g$ changes, which changes the current $I$. This causes more particles to either enter or leave the cell, which changes membrane potential $V_m$. Membrane potential $V_m$ asymptote toward equilibrium potential $E_{\text{ion}}$. At steady-state, the net current should be zero.

If there is a delayed rectifier potassium channel, the membrane potential may undershoot the equilibrium potential.

Action Potential

Voltage-gated sodium channels have three states: closed, open, and inactivated. When depolarizing stimulus brings the membrane to a threshold potential, the voltage-gated sodium channels rapidly open, allowing Na⁺ to enter the cell and further depolarize the membrane. This depolarization triggers additional sodium channels to open through positive feedback, creating the action potential. Shortly after opening, the channel becomes inactivated, preventing further Na⁺ influx even if the membrane remains depolarized. The channel cannot reopen until the membrane repolarizes toward its resting potential, at which point it returns to the closed state.

Delayed rectifier potassium channels are voltage-gated channels that open in response to depolarization. As the voltage-gated sodium channels are inactivated, the potassium channels open up, allowing the membrane to return back toward its resting potential. This is an example of a negative feedback loop.

Conduction and Synapses

Graded potentials can only travel a short distance before diminishing in amplitude. To send signals beyond a very short distance, action potentials must be generated and propagated along the entire length of neuron.

Current enters the cell and has three pathways:

1. Down the inside of the axon ($R_\text{internal}$)
2. Through the cell membrane ($R_\text{membrane}$)
3. To the cell membrane to charge up the capacitance ($C_\text{membrane}$)

We would like current to travel down the axon, but the problem is that axons are poor conductors ($R_\text{internal}$ is high), and pathways (2) and (3) are significant drains on overall current.

These problems are solved by several adaptations:

1. Having larger axon diameters, decreasing $R_\text{internal}$
2. Having no open ion channels between nodes, increasing $R_\text{membrane}$
3. Having a thick myelin sheath, decreasing $C_\text{membrane}$

Every so often, there are gaps in the myelin sheath called nodes of Ranvier where the voltage-gated sodium channels are concentrated. These regions are where the action potential is regenerated.

Local anesthetic works by blocking action potentials in small diameter axons (like those that handle pain). It spares large diameter axons like touch and motor.