Ch1 Fundamentals

Homeostasis

Homeostasis: holding internal conditions at a steady state.

• Negative feedback mechanisms are crucial for regulating homeostasis.

Feedback Loops

Negative Feedback (more common)

A negative feedback system has four parts:

1. Sensor
2. Controlled variable
3. Controller
4. Effector

Controller logic

• The controller has a set point.
• The controller contains a comparator that compares the sensor input with the set point.

• This produces:

• an error signal (within the controller), and

• an actuating signal (sent out of the controller to the effector).

Example: keeping warm in winter

• Sensor: thermometer
• Controlled variable: temperature
• Controller: thermostat
• Effector: furnace/heater

If the room temperature is no smaller than the set point:

• error signal is 0 / +, and
• the actuating signal will not be sent.

Negative feedback variables (examples)

• body temperature
• mood
• plasma concentration of H₂O, H⁺, Ca²⁺, glucose

Example: body temperature regulation

• Controlled variable: body temperature
• Sensor: thermoreceptors
• Controller: hypothalamus

• Effectors:

• skeletal muscles

• skin arterioles (thin blood vessels in skin; dilation cools body temperature)
• sweat glands
• etc.

Positive Feedback

A positive feedback system has four parts:

1. Sensor
2. Output variable
3. Effector
4. Amplifier

Key differences from negative feedback:

• No controlled variable
• No set point

Properties

• Plateau: maximum value of the effector output
• Threshold: level of the output variable at which point the system rapidly drives toward the plateau

Examples

• Action potential (voltage-gated Na⁺ channels)
• Labor and childbirth

Labor and childbirth (mapped to the four parts)

• Output variable: pressure in cervix and uterine wall
• Sensor: pressure-sensitive sensory neurons in cervix and uterine wall
• Amplifier: hypothalamus / pituitary
• Actuating signal: oxytocin
• Effector: uterine smooth muscle
• Plateau: the maximum force that the uterine smooth muscle can generate

Transport

Three primary factors that drive movement

1. Pressure (e.g., heart pumping blood)
2. Concentration (diffusion)
3. Electrical charge (e.g., voltage-gated channels)

Transport across a semipermeable membrane

Without protein

• oxygen gas
• steroid hormones
• water (in small amount)

With protein

• ions
• glucose
• water (in large amount)

Water diffusion (osmosis)

• Isotonic: generally OK
• Hypotonic: more solute in the cell → the cell will swell
• Hypertonic: less solute in the cell → the cell will shrink

Factors for ion transport

• Concentration gradient
• Charge gradient

Typical ion distributions in a real cell

• K⁺ concentration is higher inside the cell
• Na⁺ concentration is lower inside the cell
• K⁺ is often closer to equilibrium

Ways of Transport

Passive transport

• Simple diffusion

• Diffusion via channel

• Channels allow diffusion through the membrane

• Examples:

  1. ion channels
  2. aquaporins
  3. Uniporter carrier protein

• allows passive movement

Active transport

• Primary active transport

• Example: Na⁺/K⁺ ATPase (3 Na⁺ out, 2 K⁺ in)

• Takes ~30% of total energy (context-dependent)

• Secondary active transport

• Example: SGLT1 and SGLT2 are Na⁺/glucose cotransporters

  • Na⁺ moves down its gradient
  • glucose moves up its gradient

Endocytosis

• engulfing extracellular substances
• internalization of transmembrane proteins

Exocytosis

• secretion of proteins or other messengers
• trafficking of transmembrane proteins to membrane

Cell-to-Cell Communication

The chemical messenger / ligand / first messenger binds to a specific receptor molecule.

Ligand types

• Lipid-soluble messenger — binds to receptors in cytoplasm or nucleus

• Water-soluble messenger — binds to receptors on the cell membrane

• example: ionotropic receptors (nAChR)

GPCRs (G-Protein Coupled Receptors)

Core mechanism

1. Receptor associated with heterotrimeric G protein (α, β, γ)
2. Ligand binding causes α subunit to bind GTP instead of GDP
3. GTP binding causes α subunit to dissociate from β, γ subunits
4. α subunit interacts with and activates a transmembrane enzyme or ion channel
5. α subunit has intrinsic GTPase activity, turning itself off by catalyzing cleavage of the third phosphate in GTP
6. Subunits reassociate with each other and receptor

Example

• oxytocin binds with a GPCR

Example signaling chain (cAMP pathway)

1. Gα subunit activates adenylyl cyclase
2. Adenylyl cyclase catalyzes production of cAMP from ATP
3. cAMP binding activates cAMP-dependent protein kinase (Protein Kinase A, PKA)

Key notes

• importance of second messengers in signaling pathways
• amplification of a signal
• key role of kinases in many signaling pathways

Hormones and the Endocrine System

Hormone

A hormone is a secreted molecule that travels through the blood to target cell(s), exerting effects based on interaction with a receptor.

• Some hormones can act as neurotransmitters.

Endocrine system

One of the two main physiological control systems (with the nervous system).

Roles include widely varying physiological functions such as:

• homeostatic regulation of ions
• energy availability
• coordinated changes such as growth and development

Endocrine vs nervous system

• Nervous system (NS): targeted at one cell via synapse, fast, shorter duration
• Endocrine system (ES): hormones secreted by endocrine glands, affect more cells, slower, longer duration

Hypothalamus and Pituitary

The hypothalamus (with the pituitary gland below it):

• Hypothalamus has neurosecretory cells whose axons release hormones into capillaries in the posterior pituitary.
• Hypothalamus also has neurosecretory cells whose axons release hormones into the portal system that transports blood a short distance to the anterior pituitary.

Stress Response Pathway (HPA axis)

Stress (psychosocial stress, temperature, fasting, exercise, and anything that is a threat to homeostasis):

[ \text{Stress} \rightarrow \text{hypothalamus releases CRH} \rightarrow \text{anterior pituitary releases ACTH} \rightarrow \text{adrenal cortex releases cortisol} \rightarrow \text{most tissues respond to cortisol} ]

Adrenal gland hormones

The adrenal gland releases several hormones.

• Inner-most section: Medulla

• releases epinephrine and norepinephrine

• Outer section: Cortex

• Inner: Zona reticularis

  • releases androgens and small amount of cortisol

  • Mid: Zona fasciculata

  • releases cortisol and small amount of androgens

  • Outer: Zona glomerulosa

  • releases aldosterone

Solubility

• CRH, ACTH are water soluble
• cortisol is lipid soluble

Cortisol effects

• stimulation of liver cell uptake of amino acids and conversion to glucose
• stimulation of triglyceride breakdown in adipocytes
• inhibition of inflammation
• inhibition of nonessential functions (e.g., growth and reproduction)

Negative feedback

Cortisol inhibits CRH and ACTH release and thus inhibits cortisol release.

Insulin Pathway

Components

• Sensor: β islet cells in pancreas
• Controller: β islet cells in pancreas
• Actuating signal: insulin
• Effectors: skeletal muscle, adipocytes, liver cells
• Controlled variable: blood plasma glucose level

β-cell mechanism

• β islet cells have GLUT2 transmembrane protein (glucose transporter)
• glucose is converted into ATP
• ATP binds to ATP-sensitive K⁺ channel ((\text{K}_{\text{ATP}}))
• K⁺ stops flowing out
• membrane potential increases (depolarization)
• voltage-gated Ca²⁺ channels open
• Ca²⁺ flows into the cell (positive feedback in increasing membrane potential)
• exocytosis releases insulin

Insulin effects (examples)

• insulin activates insulin receptor (transmembrane, tyrosine kinase)

• stimulates GLUT4 exocytosis → increases glucose uptake (skeletal muscle)

• insulin activates insulin receptor

• initiates glycogenesis (glucose → glycogen) (liver cell; glucose transported via GLUT2)

Glucagon Pathway

Components

• Sensor: α islet cells in pancreas
• Controller: α islet cells in pancreas
• Actuating signal: glucagon
• Effectors: liver cells
• Controlled variable: blood plasma glucose level

Mechanism

• glucagon binds to glucagon receptor (GPCR)
• increases cAMP
• promotes glucose production from glycogen (glycogenolysis)
• glucose flows out of the cell via GLUT2

Diabetes Mellitus

Plasma glucose levels are very high.

• Type 1: problem with β islet cells → not enough insulin produced (often autoimmune)
• Type 2: insulin insensitivity in skeletal muscle, adipocytes, and/or liver cells

Ca²⁺ is Important

Ca²⁺ is important for:

1. insulin release
2. parathyroid hormone signaling
3. neuronal signaling
4. muscle contraction

Ca²⁺ Regulation

System components

Includes:

1. parathyroid glands
2. bones
3. kidneys
4. GI tract

Negative feedback loop

• Controlled variable: plasma levels of Ca²⁺
• Sensor: parathyroid gland cells via CaSR (Calcium Sensing Receptor)
• Controller: parathyroid gland
• Actuating signal: PTH

Effectors

1. Bone

2. osteoclasts break down calcified extracellular matrix in bone tissue → releases Ca²⁺

3. Kidney epithelial cells

4. increases Ca²⁺ reabsorption

5. Kidney endocrine cells

6. release 1,25-dihydroxy vitamin D (lipid soluble)

7. binds Vitamin D Receptor (VDR) in intestine, enters nucleus
8. increases TRPV6 transcription
9. TRPV6 merges with the cell membrane; TRPV6 is a Ca²⁺ channel that takes up Ca²⁺

Parathyroid Glands

Key facts

• located near the throat
• express a transmembrane receptor called Calcium Sensing Receptor (CaSR)
• CaSR is a GPCR

CaSR → PTH regulation

• Ca²⁺ binds to CaSR and initiates a pathway that inhibits ParaThyroid Hormone (PTH) release

PTH

• PTH is a hydrophilic hormone that binds to a GPCR

PTH Pathways

1) Adenylyl cyclase / cAMP / PKA pathway

2) Phospholipase C (PLC) pathway

1. activates phospholipase C

2. produces:

3. IP₃ (releases Ca²⁺ from ER)

4. DAG (activates Protein Kinase C)
5. Ca²⁺ (released downstream)