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
   • Cystic Fibrosis
4. Cell Communication
   • Chemical Messengers
5. Endocrine System
6. Neuronal Signaling
   • Membrane Potential
   • Equilibrium Potential
   • Current
   • Action Potential
   • Conduction and Synapses
   • Neurotransmitters
7. Nervous System
   • Activation Pathways
   • Visceral and Somatic Motor

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.

Here are the intracellular and extracellular concentrations of ions:

Active Transport

Primary active transport uses ATP to move molecules against their concentration gradient.

An example is the sodium-potassium pump (Na+/K+-ATPase), 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).

For example, the sodium–glucose cotransporter (SGLT) uses the energy of Na+ moving down its electrochemical gradient to transport glucose into the cell against its concentration gradient. This process is driven in part by the negative resting membrane potential.

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.

Cystic Fibrosis

Cystic fibrosis is a genetic disorder caused by mutations in the CFTR gene, which encodes a chloride channel protein. Cystic fibrosis causes the chloride channel to be malformed and marked by degradation, preventing it from reaching the cell membrane.

Chloride is trapped inside of the cell, preventing water from moving outside to thin the mucus. Chloride is also not reabsorbed, resulting in very salty sweat.

In the pancrease, the lack of chloride secretion limits Na+ secretion, which then limits water secretion, causing pancreatic exocrine secretion to be too thick. Finally, this causes digestive enzymes to not be secreted into the GI track.

Some treatments for cystic fibrosis include:

1. Drugs that chaperone CTFR to the membrane to prevent its premature degradation
2. Drugs that increase conductance of Fl

Cell Communication

Cell communication occurs through gap junctions, surface protein interaction, and chemical messengers.

Chemical Messengers

Chemical communication occurs in the nervous system and the endocrine system.

Steps:

1. Ligand released
2. Ligand binds to receptor
3. Receptor protein have conformational change

Receptors differ in the number of ligands they can bind to (specificity) and their affinity for those ligands.

If there are multiple types of ligands that can bind to the same receptor, then they will compete for binding. Some ligands are agonists, which activate the receptor, while others are antagonists, which block the receptor. Receptors can become saturated when all of the receptors are occupied by ligands.

There are serveral types of receptor responses:

1. Ligand-gated ion channels open or close
2. Tyrosine kinase have enzymatic activity
3. Receptors interact with cytoplasmic janus kinases
4. G-protein coupled receptors activate

G-proteins contain an alpha, beta, and gamma subunit. When the first messenger binds to the receptor, it increases the affinity of the alpha subunit for guanosine triphosphate (GTP). When bound to GTP, the alpha subunit dissociates and links up with an effector protein in the membrane. Once it activates the protein, the GTP is cleaved back into GDP, allowing the alpha subunit to recombine with the G-protein group.

When adenylyl cyclase is activated by the alpha subunit, it takes in ATP and creates cyclic adenosine monophosphate (cAMP). cAMP acts as a second messenger and binds to an enzyme known as cAMP-dependent protein kinase (protein kinase A). Eventually, cAMP terminates when it is broken down to AMP.

Question: Why is this process so complicated?

The benefits of having a multistep process is (1) amplification, (2) modulation, and (3) duration.

Question: How can the same second messenger cause two different cellular responses?

Each receptor is surrounded by different effector proteins, protein kinases, and phosphatases. This allows the same second messenger to cause different responses in different compartments.

Endocrine System

The hypothalamus produces releasing factors that are released into the capillary bed in the pituitary stalk. They stimulate the anterior pituitary gland, causing it to release 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.

Hyperthyroidism causes increased metabolic rate and body temperature.

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).

Question: What happens when...

Neuronal Signaling

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.

Neuron anatomy:

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. This 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.

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

Equilibrium potential

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

Current

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.

Neutrotransmitters

Neurons communicate with each other through chemical messengers called neurotransmitters.

1. An action potential arrives at the presynaptic axon terminal.
2. The depolarization causes voltage-gated calcium channels to open.
3. Ca2+ enters the cell, causing exocytosis of synaptic vesicles containing neurotransmitters.
4. The neurotransmitters diffuse across the synaptic cleft and bind to receptors on the postsynaptic cell.

Nervous System

The central nervous system (CNS) is comprised of the brain and spinal cord.

• The hypothalamus controls the pituitary hormones.
• The medulla controls breathing and heart rate.

The peripheral nervous system (PNS) has three components:

1. The somatic controls voluntary movements by skeletal muscles.
2. The autonomic controls involuntary functions by smooth muscles and glands.
3. The enteric controls the gastrointestinal system (gut).

The autonomic nervous system can be divided into the sympathetic, which is responsible for the fight-or-flight response, and the parasympathetic, which is responsible for rest-and-digest functions.

Activation Pathways

In the somatic nervous system, the axon releases acetylcholine (ACh), which binds to nicotinic ACh receptors on the skeletal muscle, causing it to contract.

In the automatic nervous system, preganglionic neurons releases ACh, which binds to nicotinic ACh receptors on the postganglionic neuron. The postganglionic then releases a different neurotransmitter depending on whether it is part of the sympathetic or parasympathetic nervous system.

In the sympathetic nervous system, the postganglionic neuron then releases norepinephrine, which binds to adrenergic receptors on the target tissue. The adrenergic receptors can be either alpha or beta, and they can have different effects on the target tissue. Alpha-1 adrenergic receptors cause vasoconstriction, while beta-2 adrenergic receptors cause vasodilation.

In the parasympathetic nervous system, the postganglionic neuron then releases ACh, which binds to muscarinic ACh receptors on the target tissue

Visceral and Somatic Motor

Muscles are made of muscle fibers, which contain myofibrils composed of repeating sarcomeres. The sarcomere is the basic contractile unit of muscle and contains thin filaments (actin) anchored to the zig-zagging Z lines and thick filaments (myosin) anchored at the middle M line. The actin contains regulatory proteins (troponin and tropomyosin) which control whether it can bind to myosin.

The neuromuscular junction is the synapse between a motor neuron and a skeletal muscle fiber. The motor neuron releases ACh, which binds to nicotinic ACh receptors on the muscle fiber, causing depolarization of the sarcolemma and propagation of an action potential.

T-tubules conduct the action potentials, allowing them to reach the interior of the cell. In the T-tubules, depolarization activates dihydropyridine (DHP) receptors. They are mechanically coupled to ryanodine receptors on the sarcoplasmic reticulum, so their conformational change causes Ca++ to release from the sarcoplasmic reticulum.

Calcium binds to troponin, causing tropomyosin to shift away from myosin-binding sites on actin. A crossbridge forms between the myosin heads and the actin when myosin has ADP and Pi bound and troponin has Ca++ bound. This causes muscle contraction.

Muscular force is correlated with (1) the concentration of intracellular calcium as well (2) the number of cross-bridges per second.