KPE260 Week 2: Cell Signaling PART 2 - PATHWAYS

epithelial cells

Cells that line hollow organs and tubes and regulate the absorption and secretion of substances.

What is the apical membrane of an epithelial cell?

The side that faces the lumen.

basolateral membrane

The side that faces the basement membrane/interstitial fluid side.

paracellular pathway

Movement of molecules between epithelial cells, through the spaces/tight junction areas between them.

transcellular pathway

Movement of molecules through an epithelial cell.

Path: Apical membrane → cytoplasm → basolateral membrane

difference between paracellular and transcellular transport

Paracellular = BETWEEN cells

Transcellular = THROUGH cells

How can active Na⁺ transport affect water movement across an epithelium?

Active Na⁺ transport changes the osmolarity across the epithelium (water follows sodium)

examples of chemical messengers

• Hormones

• Neurotransmitters

• Other signalling molecules

receptor

protein or glycoprotein that recognizes and binds a signalling molecule.

Receptors can be:

• On the plasma membrane

• Inside the cell

Why doesn't every cell respond to the same chemical messenger?

A cell needs the correct receptor to respond to that messenger.

intracellular receptors located

• Cytosol

• Nucleus

intracellular receptors function

They can affect gene activity/transcription, ultimately changing which proteins the cell produces.

plasma membrane receptors

Transmembrane proteins that span the entire membrane.

Chemical messengers bind to the extracellular part, while the intracellular part participates in signalling.

three important characteristics of receptors

1. Specificity

2. Affinity

3. Saturation

receptor specificity

Specificity refers to the receptor's ability to recognize and bind the appropriate ligand.

receptor affinity

Affinity describes how strongly a ligand binds to its receptor.

receptor saturation

Saturation occurs because there is a limited number of receptors.

Once most receptors are occupied, adding more ligand produces little additional binding.

difference between specificity and affinity

Specificity = whether the receptor recognizes the correct ligand

Affinity = how strongly it binds the ligand

upregulation

Increasing the number of receptors on/in a cell.

= Can make the cell more responsive to a signal.

downregulation

decreasing the number of receptors

= can make the cell less responsive to a signal

agonist

a substance thats similar to the natural ligand & activates the receptor

• ex. epinephrine

• morphine

antagonist

a substance that blocks a receptor without activating it

• beta blockers

• antihistamines

signal transduction

the process of converting an extracellular signal to an intracellular response

basic steps of cell signalling

Ligand binds → receptor activation → intracellular signalling → cellular response

types of cellular responses that signalling produces

• Membrane permeability

• Transport

• Electrical state

• Metabolism

• Secretion

• Cell growth/proliferation

• Differentiation

• Contraction

lipid-soluble messengers

Chemical messengers that can dissolve in lipids and cross the plasma membrane.

Examples:

• Steroid hormones

• Thyroid hormone

Where do lipid-soluble messengers bind?

Intracellular receptors in the cytosol or nucleus.

How do lipid-soluble messengers produce a genomic response?

Hormone crosses membrane → binds intracellular receptor → affects gene transcription → new protein is produced

characteristics of genomic responses

• Slower

• Longer-lasting

Why can't water-soluble messengers simply diffuse through the plasma membrane?

The inside of the lipid bilayer is hydrophobic, so water-soluble molecules cannot readily cross it.

Where do water-soluble messengers bind?

Plasma membrane receptors.

first messenger

The extracellular signalling molecule that binds to a receptor.

• ex. epinephrine

second messenger

An intracellular molecule that helps carry and/or amplify the signal after receptor activation.

• ie. cAMP

• DAG

• IP₃

• Ca²⁺

basic cAMP signalling pathway**

Ligand → GPCR → Gs → adenylyl cyclase → cAMP → PKA → phosphorylation → cellular response

function of Gs in the cAMP pathway

The activated Gs protein activates adenylyl cyclase.

function of adenylyl cyclase

converts ATP to cAMP

cAMP function

• second messenger

• helps carry the signal inside the cell

what does cAMP activate

protein kinase A (PKA)

PKA function

PKA phosphorylates proteins, which can change their activity and produce a cellular response.

signal amplification

When a small extracellular signal produces a much larger intracellular response.

How signal amplification works

One activated receptor can activate many signalling molecules/enzymes, creating a cascade that greatly increases the response.

Why is signal amplification useful?

It allows a small amount of signalling molecule to create a large cellular effect.

Gq signalling pathway

Ligand → receptor → Gq → PLC → PIP₂ → DAG + IP₃

What Gq activates

Phospholipase C (PLC).

PLC function

PLC breaks down the membrane phospholipid:

PIP₂ → DAG + IP₃

what do DAG and IP₃ share

second messengers

DAG function

activates protein kinase C (PKC).

PKC then phosphorylates proteins, contributing to the cellular response.

IP₃ function

promotes the release of Ca²⁺ from the endoplasmic reticulum.

Why can Ca²⁺ act as a second messenger?

Changes in intracellular Ca²⁺ concentration can activate proteins and enzymes and produce a cellular response.

some ways cytosolic Ca²⁺ can increase

• Ca²⁺ channels open in the plasma membrane

• Ca²⁺ is released from the ER

• IP₃ causes Ca²⁺ release

• Voltage-gated Ca²⁺ channels open

• Ca²⁺ removal from the cell can be reduced

What happens when Ca²⁺ binds to calmodulin?

Ca²⁺ causes calmodulin to change shape and become activated.

The Ca²⁺-calmodulin complex can then activate or inhibit different proteins/enzymes.

Why a cell needs to terminate a signal

to prevent continuous stimulation/overstimulation

how second messengers are broken down

phosphodiesterase

• cAMP to AMP

what can happen to the first messenger to terminate signalling?

• broken down by enzymes

• taken up by cells

• diffuse away

How can receptor phosphorylation help terminate signalling?

Phosphorylation can alter the receptor so that it:

• Has lower affinity for the messenger

• Releases the messenger

• Can no longer effectively interact with G proteins

How can endocytosis terminate a signalling pathway?

The receptor and bound messenger can be removed from the plasma membrane through endocytosis, reducing signalling.

Pseudohypoparathyroidism

PTH is present, but the signalling pathway doesn't respond properly because of Gsα dysfunction.

autocrine

Acts on the same cell that released it

paracrine

Through extracellular fluid to nearby cells

endocrine

long distance/blood

gap junction

• Direct connection between neighboring cells

  Allow material to move directly between cells (ie. ions, water, small molecules)

  Important in epithelial tissue

  
  

Tight junction

• Prevents substances to move freely passing between cells

  Important in epithelial tissue