Homeostasis in Mammals

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Components of a Homeostatic Control System

Every homeostatic control loop involves these key components:

1. Receptors (or sensors)

• These detect changes in conditions
• They monitor specific factors like temperature, glucose levels, or water content
• Receptors can detect both internal stimuli (changes inside the body) and external stimuli (changes in the environment around the body)

2. Coordination systems

• These transfer information between different parts of the body
• There are two coordination systems in mammals:
  • Nervous system - sends information as electrical impulses traveling along nerve cells (neurones). This is fast but usually short-lived.
  • Endocrine system - sends information as chemical messengers called hormones that travel in the blood. This is slower but usually longer-lasting.

3. Effectors

• These carry out responses to bring conditions back to normal
• The main effectors are:
  • Muscles - can contract or relax
  • Glands - can release hormones or other substances

How Negative Feedback Works

Negative feedback loops keep physiological factors within certain limits, allowing them to fluctuate around a set point (ideal value). Here's how it works:

1. The factor (like body temperature) is continuously monitored by receptors
2. If the factor increases above the set point, receptors detect this change
3. Information is sent through the coordination system to the effectors
4. Effectors respond in a way that makes the factor decrease back toward the set point
5. If the factor decreases below the set point, the opposite happens - effectors respond to make the factor increase

This creates a cycle where the factor is constantly being adjusted to stay close to the ideal value.

Why Convert Ammonia to Urea?

Ammonia is very soluble and highly toxic to body cells. If ammonia builds up in the blood, it causes serious problems:

• It dissolves in blood to form alkaline ammonium hydroxide, which disrupts blood pH
• It interferes with cell metabolism (including respiration)
• It disrupts cell signaling processes

To prevent these problems, the liver immediately converts ammonia into urea:

• Urea is less soluble than ammonia
• Urea is much less toxic than ammonia
• The liver combines ammonia with carbon dioxide to produce urea

The chemical equation is: 2NH₃ + CO₂ → CO(NH₂)₂ + H₂O

Urea then travels in the blood to the kidneys, where it is removed from the body in urine.

Internal Structure of the Kidney

Each kidney has several distinct layers and regions:

Fibrous capsule - The tough outer layer that surrounds and protects the kidney

Cortex - The outer region beneath the fibrous capsule. This area contains:

• The glomerulus (a knot of blood capillaries)
• Bowman's capsule (a cup-shaped structure around the glomerulus)
• Proximal convoluted tubule (the first twisted section of the nephron)
• Distal convoluted tubule (the second twisted section of the nephron)

Medulla - The inner region of the kidney. This area contains:

• Loop of Henle (a hairpin-shaped section of the nephron)
• Collecting duct (where urine collects from multiple nephrons)

Renal pelvis - The central cavity where the ureter joins the kidney. Urine collects here before flowing into the ureter.

Branches of the renal artery and renal vein - These blood vessels branch extensively throughout the kidney to supply blood to each nephron.

Parts of the Nephron

Each nephron consists of several distinct sections:

Glomerulus

• A tight knot of blood capillaries
• Located at the start of the nephron in the cortex
• Blood enters through a wider arteriole and leaves through a narrower arteriole
• This creates high pressure that forces substances out of the blood

Bowman's capsule

• A cup-shaped structure that surrounds the glomerulus
• Collects the fluid (called filtrate) that is forced out of the blood
• Located in the cortex

Proximal convoluted tubule (PCT)

• The first twisted section of the nephron tube after the Bowman's capsule
• "Proximal" means nearest to the start
• "Convoluted" means coiled or twisted
• This is where most reabsorption of useful substances occurs
• Located in the cortex

Loop of Henle

• A long, hairpin-shaped (U-shaped) section of the nephron
• Descends from the cortex down into the medulla, then loops back up
• Plays a key role in concentrating urine by reabsorbing water and salts

Distal convoluted tubule (DCT)

• The second twisted section of the nephron tube
• "Distal" means furthest from the start
• Fine-tunes the reabsorption of water and salts
• Located in the cortex

Collecting duct

• A tube that receives filtrate from multiple nephrons
• Runs from the cortex down through the medulla to the renal pelvis
• This is where final water reabsorption occurs, concentrating the urine
• Urine flows from here into the renal pelvis, then into the ureter

Stage 1: Ultrafiltration in the Bowman's Capsule

Ultrafiltration is the process where small molecules are filtered out of the blood under high pressure.

How ultrafiltration works:

1. Blood enters the glomerulus at high pressure because:

   • It comes directly from the renal artery (connected to the aorta)
   • The arteriole entering the glomerulus is wider than the arteriole leaving it
   • This causes a build-up of pressure

2. The high pressure forces small molecules out of the blood capillaries and into the Bowman's capsule

3. To get into the Bowman's capsule, substances must pass through three layers:

   Layer 1: Capillary endothelium

   • The wall of the blood capillary
   • Contains thousands of tiny holes
   • Allows small molecules through but not blood cells

   Layer 2: Basement membrane

   • A mesh of collagen and glycoprotein fibers
   • Acts as a filter
   • Stops large protein molecules from passing through

   Layer 3: Bowman's capsule epithelium

   • Made of special cells called podocytes
   • These cells have finger-like projections with gaps between them
   • Allows fluid through into the capsule

4. The fluid that enters the Bowman's capsule is called glomerular filtrate

What's in the glomerular filtrate? Small molecules that pass through:

• Water
• Glucose
• Amino acids
• Urea
• Inorganic ions (mainly sodium, potassium, and chloride ions)

Substances that stay in the blood:

• Red blood cells (too large)
• White blood cells (too large)
• Platelets (too large)
• Large proteins (blocked by the basement membrane)

The role of water potential:

Ultrafiltration is driven by differences in water potential:

• Water potential is affected by pressure and solute concentration
• High pressure increases water potential
• High solute concentration decreases water potential

In the glomerulus:

• The blood has HIGH pressure (raising water potential) but HIGH solute concentration (lowering water potential)
• The filtrate in the Bowman's capsule has LOW pressure (lowering water potential) but LOW solute concentration (raising water potential)

The effect of the pressure difference is greater than the effect of the solute concentration difference. Overall, the blood in the glomerulus has a higher water potential than the filtrate in the Bowman's capsule.

Therefore, water moves down the water potential gradient from the blood into the Bowman's capsule, carrying dissolved substances with it.

Stage 2: Selective Reabsorption in the Proximal Convoluted Tubule

Many substances in the glomerular filtrate are actually useful to the body and need to be kept. Selective reabsorption is the process of taking these useful substances back from the filtrate and returning them to the blood.

This happens mainly in the proximal convoluted tubule (PCT).

Substances reabsorbed in the PCT:

• All glucose - none should be left in the urine
• All amino acids
• Most water (about 85%)
• Most inorganic ions (the exact amounts reabsorbed depend on the body's needs)
• Some vitamins

Substances NOT reabsorbed:

• Urea - this waste product stays in the filtrate and leaves the body in urine

How reabsorption works:

The PCT epithelial cells are specially adapted for reabsorption. They work through a combination of active transport and diffusion:

1. At the basal membrane (the side facing the blood capillaries):

   • Sodium-potassium pumps use energy (ATP) to actively transport sodium ions out of the epithelial cells into the blood
   • This lowers the sodium concentration inside the cells

2. At the luminal membrane (the side facing the filtrate):

   • Because sodium concentration is now low inside the cells, sodium ions diffuse from the filtrate into the cells down their concentration gradient
   • Sodium ions cannot pass through freely - they must use special co-transporter proteins
   • Each co-transporter protein carries one sodium ion AND one other molecule (like glucose or an amino acid) into the cell
   • This is called co-transport

3. Movement into the blood:

   • Once inside the epithelial cells, glucose and amino acids diffuse down their concentration gradients through the basal membrane into the blood
   • They pass through transport proteins in the basal membrane

4. Water follows:

   • As solutes (glucose, amino acids, ions) move from the filtrate into the blood, the water potential of the filtrate increases and the water potential of the blood decreases
   • This creates a water potential gradient
   • Water moves by osmosis from the filtrate, through the epithelial cells, into the blood

The end result is that all the useful substances and most of the water are returned to the blood, while urea and excess substances remain in the filtrate, which will eventually become urine.

Bowman's Capsule Adaptations

Feature 1: Capillary endothelium with pores

• Function: Allows small molecules to pass through while retaining blood cells
• The thousands of tiny pores create a large surface area for filtration

Feature 2: Basement membrane

• Function: Acts as a molecular filter
• Prevents large proteins from leaving the blood
• Ensures only molecules below a certain size enter the filtrate

Feature 3: Podocyte cells with gaps

• Function: Allows filtrate to flow into the capsule space
• The finger-like projections increase surface area
• Gaps between projections provide routes for fluid flow

Feature 4: High blood pressure in glomerulus

• Function: Provides the force needed for ultrafiltration
• Created by the difference in arteriole diameters
• Ensures efficient filtration

Proximal Convoluted Tubule Adaptations

Feature 1: Microvilli on luminal membrane

• Function: Greatly increase surface area for reabsorption
• Each cell has thousands of these tiny projections
• More surface area means more co-transporter proteins can fit, speeding up reabsorption

Feature 2: Many co-transporter proteins in luminal membrane

• Function: Enable glucose and amino acids to be reabsorbed along with sodium ions
• Different types of co-transporter proteins transport different molecules
• Ensures all useful solutes can be recovered from the filtrate

Feature 3: Many mitochondria

• Function: Provide ATP energy for active transport
• The sodium-potassium pumps in the basal membranes require lots of energy
• More mitochondria means more ATP can be produced

Feature 4: Tightly packed cells

• Function: Prevents substances from leaking between cells
• Ensures all substances must pass through the cells to be reabsorbed
• Allows precise control over what is reabsorbed

Feature 5: Close proximity to blood capillaries

• Function: Provides a short diffusion distance
• Reabsorbed substances quickly enter the bloodstream
• Maintains concentration gradients for efficient reabsorption

The Role of Each Component

Hypothalamus

• Contains receptor cells called osmoreceptors
• These detect changes in water potential of the blood
• When blood water potential decreases (blood becomes too concentrated), osmoreceptors detect this
• The hypothalamus then sends signals to the posterior pituitary gland

Posterior pituitary gland

• Releases the hormone ADH into the blood when signaled by the hypothalamus
• The amount of ADH released depends on how concentrated the blood is
• More concentrated blood → more ADH released
• Less concentrated blood → less ADH released

Antidiuretic hormone (ADH)

• A hormone that increases water reabsorption in the collecting ducts
• "Anti-diuretic" means it prevents the production of large volumes of dilute urine
• Travels in the blood to the kidneys

Aquaporins

• Channel proteins in the cell membranes of collecting duct cells
• Water molecules pass through these channels by osmosis
• When ADH binds to receptors on collecting duct cells, it causes more aquaporins to be inserted into the cell membranes
• More aquaporins = more water can be reabsorbed

Collecting ducts

• The final part of the nephron where water reabsorption is controlled
• When ADH levels are high, collecting duct cells have many aquaporins in their membranes
• Water moves from the filtrate through the aquaporins into the cells, then into the surrounding blood
• This concentrates the urine and conserves water

How Osmoregulation Works

When the body needs to conserve water (e.g., when dehydrated):

1. Blood water potential decreases (blood becomes more concentrated)
2. Osmoreceptors in hypothalamus detect this change
3. Hypothalamus signals the posterior pituitary gland
4. Posterior pituitary releases more ADH into the blood
5. ADH travels to the kidneys
6. ADH binds to receptors on collecting duct cells
7. This causes more aquaporins to be inserted into the cell membranes
8. More water is reabsorbed from the filtrate into the blood
9. A small volume of concentrated urine is produced
10. Blood water potential increases back to normal

When the body needs to remove excess water (e.g., after drinking a lot):

1. Blood water potential increases (blood becomes more dilute)
2. Osmoreceptors in hypothalamus detect this change
3. Hypothalamus reduces signals to the posterior pituitary gland
4. Posterior pituitary releases less ADH into the blood
5. Less ADH reaches the kidneys
6. Fewer aquaporins are present in collecting duct cell membranes
7. Less water is reabsorbed from the filtrate
8. A large volume of dilute urine is produced
9. Blood water potential decreases back to normal

This is an example of negative feedback - changes in blood water potential trigger responses that bring it back to normal.

Cell Signaling by Glucagon

When blood glucose concentration is too low, the pancreas releases glucagon. This hormone acts on liver cells to increase blood glucose. The way glucagon works is a good example of cell signaling - how hormones communicate with cells to trigger responses.

The glucagon signaling pathway - step by step:

Step 1: Hormone binding

• Glucagon molecules in the blood bind to specific receptor proteins on the surface of liver cells
• These receptors are in the cell surface membrane
• When glucagon binds, the receptor protein changes shape (conformational change)

Step 2: G-protein activation

• The shape change in the receptor activates a protein inside the cell called a G-protein
• The G-protein is attached to the inner surface of the cell membrane
• When activated, the G-protein moves along the membrane

Step 3: Adenylyl cyclase stimulation

• The activated G-protein binds to and activates an enzyme called adenylyl cyclase
• Adenylyl cyclase is also in the cell membrane

Step 4: Formation of cAMP (second messenger)

• Adenylyl cyclase converts ATP into cyclic AMP (cAMP)
• cAMP is called a "second messenger" because:
  • The "first messenger" is the hormone (glucagon) outside the cell
  • The "second messenger" (cAMP) carries the signal inside the cell
• Many cAMP molecules are produced from one activated adenylyl cyclase

Step 5: Activation of protein kinase A

• cAMP molecules bind to and activate an enzyme called protein kinase A
• Each cAMP molecule can activate one protein kinase A enzyme

Step 6: Enzyme cascade begins

• Protein kinase A activates other enzymes by adding phosphate groups to them (phosphorylation)
• Each activated enzyme goes on to activate many more enzymes
• This creates a cascade (like a waterfall) where the signal gets amplified

Step 7: Amplification

• At each step, one activated enzyme activates many other enzymes
• For example: 1 glucagon molecule → many cAMP molecules → many protein kinase A enzymes → many other enzymes activated
• This means a tiny signal (a few glucagon molecules) produces a huge response

Step 8: Cellular response

• The final enzyme in the cascade catalyzes the breakdown of glycogen into glucose
• Glycogen is a storage carbohydrate made of many glucose molecules joined together
• Breaking down glycogen releases lots of glucose molecules
• This glucose is released into the blood, increasing blood glucose concentration

Negative Feedback Control of Blood Glucose

Blood glucose concentration is maintained through negative feedback involving two hormones: insulin and glucagon.

When blood glucose is too HIGH (e.g., after eating a meal):

1. Receptors in the pancreas detect the high blood glucose concentration
2. The pancreas releases more insulin into the blood
3. Insulin travels to its target cells: muscle cells and liver cells

Effects of insulin on muscle cells:

• Insulin causes muscle cells to take up more glucose from the blood
• The glucose is used in respiration to provide energy
• Some glucose is converted to glycogen for storage

Effects of insulin on liver cells:

• Insulin stimulates liver cells to take up more glucose from the blood
• The glucose is converted into glycogen for storage (this process is called glycogenesis)
• Insulin also increases the rate of respiration in liver cells, using up glucose

4. As a result, blood glucose concentration decreases back to normal
5. When blood glucose returns to normal, insulin secretion decreases

When blood glucose is too LOW (e.g., during exercise or between meals):

1. Receptors in the pancreas detect the low blood glucose concentration
2. The pancreas releases more glucagon into the blood
3. Glucagon travels to its target cells: liver cells (it does not affect muscle cells)

Effects of glucagon on liver cells:

• Glucagon stimulates liver cells to break down glycogen into glucose (this process is called glycogenolysis)
• The glucose is released into the blood
• Glucagon also stimulates liver cells to make new glucose from non-carbohydrate sources like amino acids and glycerol (this process is called gluconeogenesis)

4. As a result, blood glucose concentration increases back to normal
5. When blood glucose returns to normal, glucagon secretion decreases

This system is an example of negative feedback because:

• An increase in blood glucose triggers a response (insulin release) that makes blood glucose decrease
• A decrease in blood glucose triggers a response (glucagon release) that makes blood glucose increase
• The system constantly works to keep blood glucose fluctuating around an ideal set point

Urine Test Strips

Test strips can detect glucose in urine. Normally, there should be no glucose in urine because all glucose is reabsorbed in the proximal convoluted tubule. However, if blood glucose concentration rises above a level called the renal threshold, not all glucose can be reabsorbed, and some appears in urine.

How urine test strips work:

Components:

• A small pad at one end of the strip contains two enzymes that are immobilized (stuck in place):
  • Glucose oxidase
  • Peroxidase
• The pad also contains a colorless chemical called a chromogen

Process:

1. The pad is dipped into a urine sample for a few seconds
2. If glucose is present in the urine, the following reactions occur:

Reaction 1:

• Glucose oxidase catalyzes the oxidation of glucose
• Glucose + Oxygen → Gluconic acid + Hydrogen peroxide
• This produces hydrogen peroxide

Reaction 2:

• Peroxidase catalyzes a reaction between hydrogen peroxide and the colorless chromogen
• Hydrogen peroxide + Chromogen (colorless) → Oxidized chromogen (colored) + Water
• This produces a brown-colored compound

3. The color of the pad is compared to a color chart
4. The color chart shows different shades from light green (no glucose) to dark brown (high glucose concentration)
5. The darker the color, the higher the glucose concentration in the urine

Limitations of urine test strips:

• They only show whether blood glucose was above the renal threshold while urine was collecting in the bladder
• They do not show the current blood glucose concentration
• There is a time delay between blood glucose changes and urine glucose changes

Blood Glucose Biosensors

A biosensor is a device that uses biological molecules (like enzymes) to detect and measure the concentration of a specific substance. Blood glucose biosensors are more accurate than urine strips and show current blood glucose levels.

How blood glucose biosensors work:

Components:

• A recognition layer containing immobilized glucose oxidase enzyme (no peroxidase needed)
• A partially permeable membrane covering the recognition layer
• An electrode (transducer) that detects electron transfers
• An amplifier
• A processor
• A digital display

Process:

1. A small sample of blood is placed on the biosensor
2. The partially permeable membrane allows only small molecules (like glucose) to reach the enzymes
3. If glucose is present, glucose oxidase catalyzes this reaction:
   • Glucose + Oxygen → Gluconic acid + Hydrogen peroxide
4. The hydrogen peroxide produced is oxidized at the electrode
5. This oxidation produces electrons
6. The electrode detects these electrons as an electrical current
7. The current is proportional to the glucose concentration - more glucose produces more current
8. The amplifier increases the current signal
9. The processor converts the current into a glucose concentration value
10. The digital display shows the blood glucose concentration in mg/cm³
11. This whole process takes only a few seconds

Advantages of biosensors:

• Show current blood glucose concentration
• Very fast results (seconds)
• More accurate than urine strips
• Can be used frequently throughout the day

Important note about enzyme specificity: Both test strips and biosensors use glucose oxidase, which is specific to glucose. This means:

• They will only produce a positive result for glucose
• Other sugars (fructose, sucrose, lactose) will not trigger a reaction
• This specificity is due to the enzyme's active site shape, which only fits glucose molecules