Cell Signalling

Question 1

What is cell signalling?

Answer 1

Transferring information from the outside of the cell to obtain a response inside the cell

• Cells communicate by sending & receiving chemical signals that can take place over short or long distances

Question 2

Four essential elements for cell signalling:

Answer 2

• Communication between cells, either prokaryotic or eukaryotic, involves four essential elements:
  1. Signalling cell
  2. Signalling molecule
  3. Receptor molecule
  4. Responding cell

Question 3

How do bacteria take up DNA from the environment?

Answer 3

• A small peptide was discovered to be continuously synthesized by pneumococcal bacterial cells
• Cells express a receptor for this peptide on the surface
• When the peptide binds to the receptor → the bacterium expresses genes that enable it to take up DNA from the environment

Question 4

How does the density of bacteria affect gene transfer

Answer 4

If a low density of bacteria →
- Signal falls below its critical threshold
- Gene expression is turned off

If a high density of the bacteria →
- Peptide is bound → the signal is relayed by signal transduction to the nucleoid region
- Genes that produce proteins involved in DNA uptake from the environment are turned on (bacteria is receiving external DNA)

Question 5

Signalling in Multicellular Organisms

Answer 5

• Cells within a multicellular organism need the same four elements to communicate:
  i. Signalling cell → e.g. cells of the adrenal glands
  ii. Signalling molecule →e.g. release of epinephrine
  iii. Receptor protein → e.g. found on cells of target organs
  iv. Responding cell → e.g. changes in physiological function such as increase heart rate

Question 6

The 4 steps of cell signalling

Answer 6

• There are four steps involved in signalling between cells
  1. Receptor activation → binding of signalling molecule
  2. Signal transduction → transmission of signal into the cell
  3. Cellular response → specific for the target cell
  4. Signal termination → stop response

Question 7

Receptor activation: External

Answer 7

Some receptors are cell surface proteins that recognizes specific molecules → ligands
- Can be an extracellular ligand → molecules secreted by cells
- Can be due to cell-to-cell contact or contact with extracellular matrix

Question 8

Receptor activation: internal

Answer 8

• Ligand travels into the cell to bind to receptor
• Once the signalling molecule is bound to the receptor on the responding cell, the receptor is turned on → activated
• Remember → no receptor = no response

Question 9

How does ligand binding work?

Answer 9

• The ligand interaction with the ligand-binding site is very similar to the substrate/active site
• When a ligand binds to the ligand-binding site on its receptor conformational change in the receptor triggers chemical reactions within the cytosol

Question 10

Signal Transduction

Answer 10

• Once activated, the receptor transmits a message to the cell through the cytoplasm → intracellular signal
• This transmits the reception of ligand binding to the receptor → the stimulus
• Message can remain in the cytosol or go to the nucleus
• A series of distinct proteins that are activated/inactivated in a particular sequence
• Often amplified (One activated receptor could create 100 second messengers. Each of those could activate 100 target proteins. Now, a single signal has triggered 10,000 responses.)

Question 11

Response and Termination

Answer 11

• The cell then responds to the signal
• Response could activate enzymes, turn on genes, signal other cells, and cause the cell to divide or change shape
• The response will depend on the cell type → depends on the specific proteins and signalling pathways in that cell
• e.g. epinephrine on heart muscle causes it to contract more forcefully & quickly, but smooth muscle cells lining the respiratory airways will relax
• Once the signal has been received and acted upon, it is terminated → stops the cellular response

Question 12

How do we classify cell communication?

Answer 12

• In multicellular organisms, communication happens between cells within the same organism
• The distance between communicating cells varies
• Cell communication is classified by distance between the signalling cell and the target cell
• Can be divided into long distance communication and short distance communication

Question 13

Endocrine Signalling

Answer 13

• Long distance communication where the signalling molecules travel through the bloodstream → endocrine signalling
• Uses chemical signalling molecules → hormones
• Produced by endocrine cells
• The target cell expresses the appropriate receptor for the hormone

Question 14

Paracrine Signalling

Answer 14

• Neighbouring cells communicate where the signalling molecule travels a short distance → paracrine signaling
• Signalling molecule moves via diffusion → typically small, water soluble
• Travel within range of ~20 cells

Question 15

Autocrine Signalling

Answer 15

• When a cell that secretes a signalling molecule is also the target cell → autocrine signaling
• Paracrine and autocrine signalling are especially important in multicellular organisms during embryonic development

Question 16

Contact-Dependent Signalling

Answer 16

• Some signalling occurs because of direct contact between neighbouring cells → contact-dependent signalling
• A transmembrane protein on the surface of one cell acts as the signalling molecule → a transmembrane protein on an adjacent cell acts as the receptor
• Also called juxtacrine signalling

Question 17

Intracellular receptors

Answer 17

• Nonpolar signalling molecules can pass through the hydrophobic core of the cell membrane
• These signals do not need a receptor on the outside of the cell
• Instead, once inside the cell, the ligand can bind to receptor proteins located in the cytosol or in the nucleus → activate the receptor

Question 18

Cell surface receptors

Answer 18

• Signalling molecules that are polar cannot cross the cell membrane
• Bind to transmembrane proteins that are cell-surface receptors
• Binding of ligand to the cell-surface receptor → change in conformation
• This activates the receptor
• Cells can express many different proteins on the surface of a cell

Question 19

What are the 3 main groups of protein that take part in cell signalling?

Answer 19

• For those proteins that take part in cell signalling → can be classified into three main groups
  1. G protein-coupled receptors → GPCRS
  2. Receptor kinases
  3. Ion channels

Question 20

Where are GPCRs found and what are its components?

Answer 20

• GPCRs are found in virtually every eukaryotic organism
• G protein-coupled receptors associate with G proteins → bind to GTP and GDP in the cytoplasm.
• G proteins are composed of three subunits:
• Alpha → a
• Part of the G protein that binds to either GDP or GTP
• Beta → B
• Gamma → Y

Question 21

What happens when GDP and GTP are bound to the alpha subunit?

Answer 21

• When the a subunit is bound to GDP → the three subunits are joined
• Binding of the G protein to GTP or GDP regulates G protein activity
• When a G protein is bound to GTP → active
• When it is bound to GDP → inactive

Question 22

GCPR activation

Answer 22

• The following steps happen when a ligand binds to a GPCR → remember, the GPCR is inactive until a ligand binds to the receptor
• Ligand binds to a GPCR → binding activates the G protein by replacing GDP with GTP
• If bound to GTP, the G protein is “on” → the signal continues to be transmitted
• The alpha subunit disassociates from the other subunits
• Binds to the target protein to activate the protein

Question 23

How is heart rate influenced by signals that activate a GPCR system?

Answer 23

Through epinephrine released from the adrenal gland (adrenaline)

1) When epinephrine binds to a GPCR on heart muscle → binding activates the G protein
2) GDP on the alpha subunit is exchanged with GTP
3) GTP-bound alpha subunit of the activated G protein then binds to and activates an enzyme in the cell membrane called adenylyl cyclase
4) This enzyme converts the nucleotide ATP into the small signalling molecule cyclic AMP → CAMP
- CAMP is a second messenger
5) CAMP binds to and activates another enzyme → protein kinase A
6) Activated PKA phosphorylates proteins in the heart → increases the rate of contraction
- As long as epinephrine is bound to the receptor → heart rate will remain high

Question 24

Overview of Signal Amplification

Answer 24

• The signals produced by activated GPCRs are amplified
• Means that a small amount of ligand can produce a large response in the target cell
• Let’s examine the epinephrine example again
• The signal is amplified in three places:
  i. Each epinephrine-bound receptor activates multiple G proteins
  ii. Each adenylyl cyclase molecule produces large amounts of cAMP
  iii. Each active protein kinase A activates multiple protein targets

Question 25

Overview of Signal Termination

Answer 25

- The time a ligand is bound to its receptor depends on how tightly the receptor holds on to it - This is known as the → binding affinty - For the epinephrine example: 1) Epinephrine leaves the receptor, which reverts to its inactive conformation → no longer activates G proteins 2) G proteins convert GTP to GDP → becoming inactive 3) This inactivates adenylyl cyclase → binding affinity 4) Enzymes in the cytosol degrade cAMP stops the activation of more protein kinase A molecules 5) Phosphatases remove phosphate groups from activated proteins → this inactivates the proteins

Question 26

Overview of Receptor Kinases

Answer 26

- A receptor kinase becomes active when the ligand binds - The receptors associate into dimers → trans-autophosphorylation - This results in the phosphorylation of another protein → transmits the signal from outside the cell to inside the cell

Question 27

Example of receptor kinase:

Answer 27

- Receptor kinase signalling is used in multiple processes - Some examples include: - The formation and elongation of structures called limb buds that become our arms and legs - Insulin signalling, allowing us to transport glucose across the plasma membrane into the cytosol - Wound healing → e.g. after a paper cut

Question 28

Receptor Kinase - Wound Healing: if there is a small paper cut the cells need to be repaired how?

Answer 28

- When blood encounters the damaged area the platelets in the blood release proteins including platelet-derived growth factor → PDGF - Repair is stimulated by PDGF → binds to PDGF receptor kinases on the surface of the cell - The receptors dimerize and become active - The phosphorylated receptors help activate other proteins in the cell - In the MAP (Mitogen activated Protein) kinase pathway, the cytoplasmic signalling protein activated is → Ras - GTP-bound Ras triggers a kinase cascade - At the end of the cascade the activated kinase enters the nucleus - Turns on expression of genes associated with cell division - The pathway is terminated when the GTP is replaced by GDP on Ras

Question 29

Ligand-Gated Ion Channel

Answer 29

- Ion channels can change the flow of ions across the cell membrane → either into (influx) or out of (efflux) the cell - Ion channels can be gated i. Ligand-gated → respond to binding of a signalling molecule ii. Voltage-gated → respond to changes of voltage in the cell iii. Mechanically-gated → respond to force applied to the cell - The gate regulates the movement of ions across the channel - Prevents the movement of the ion → gate is closed - Allows the movement of the ion → gate is open