Cell Signaling
Cell Signaling - Transferring info 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
Elements for Cell Communication
Communication between cells, either prokaryotic or eukaryotic, involves 4 essential elements
- Signalling Cell
- Signalling Molecule
- Receptor Molecule
- Responding Cell
Signalling in Bacteria
Bacteria have been observed to take up DNA from the environment
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
If a low density of bacteria → Low Peptide Levels
Signal falls below its critical threshold
Gene expression is turned off
If a high density of the bacteria → High Peptide Levels
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
What 4 elements do Multicellular Organism need to communicate?
Cells within a multicellular organism need the same 4 elements to communicate
Signalling Cell → e.g., cells of adrenal glans
Signalling Molecule → e.g., release of epinephrine
Receptor Protein → e.g., found on cells of target organs
Responding Cell → e.g., changes in physiological function such as increased heart rate
4 Steps of Cell Signalling
Steps
4 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
Cell Signalling: Receptor Activation
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
Some receptors are found inside the cell
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
The ligand interaction w/ the ligand-binding site is very similar to the substrate/active site binding in enzymes
When a ligand binds to the ligand-binding site on its receptor → conformational change in the receptor triggers chemical reactions within the cytosol
Cell Signalling: Signal Transduction
Once activated, the receptor transmits a message to the cell through the cytoplasm → Signal Transduction
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
Cell Signalling: The Response & Termination
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 relay
Once the signal has been received and acted upon, it is terminated → Stops the Cellular Response
How Far Do Signals Travel?
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
Endocrine Signalling
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
Paracrine Signalling
Neighbouring cells communicate where the signalling molecule travels a short distance → Paracrine Signalling
Signalling molecule moves via diffusion → typically small, water soluble
Travel within range of ~20 cells
Autocrine Signalling
When a cell that secretes a signalling molecule is also the target cell → Autocrine Signalling
Paracrine and autocrine signalling are especially important in multicellular organisms during embryonic development
Contact-Dependent Signalling
Some signalling occurs b/c 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
Cellular Receptors: Intracellular Receptors
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
Cellular Receptors: Cell Surface Receptors
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
For those proteins that take part in cell signalling → can be classified into 3 main groups
G protein-coupled receptors → GPCRs
Receptor Kinases
Ion Channels
G Protein-Coupled Receptors (GPCRs)
Background
GPCRs are found in virtually every eukaryotic organism
G Protein-Coupled receptors associated with G Proteins → BLANK
G Proteins are composed of 3 Subunits
Alpha → BLANK
Part of the G protein that binds to either GDP or GTP
Beta → BLANK
Gamma → BLANK
When the alpha subunit is bound to GDP → the 3 subunits are joined
Binding of the G protein to GTP or GDP regulates G protein activity
When a G protein is bound to GTP → BLANK
When it is bound to GDP → BLANK
GPCR Activation
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
Example of GPCR Activation
Heart rate can be influenced by signals that activate via a GPCR system
Through epinephrine released from the adrenal gland
Epinephrine is also known as adrenaline
What are kinases
Kinases are enzymes that phosphorylate target proteins
What happens when epinephrine binds to a GPCR on heart muscle?
binding activates the G protein
- GDP on the alpha subunit is exchanged with GTP
- GTP-bound alpha subunit of the activated G protein then binds to and activates an enzyme in the cell membrane called adenylyl cyclase
- this enzyme converts the nucleotide ATP into the small signalling molecule cyclic AMP → cAMP *adenine monophosphate
cAMP is a second messenger
cAMP binds to and activates another enzyme → protein kinase A (PKA)
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
Signal Amplification
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 3 places
Each epinephrine-bound receptor activates multiple G proteins
Each adenylyl cyclase molecule produces large amounts of cAMP
Each activate protein kinase A activates multiple protein targets
Signal Termination
Overview
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 affinity
For the epinephrine example
Epinephrine leaves the receptor, which reverts to its inactive conformation → no longer activates G proteins
G proteins convert GTP to GDP → becoming inactive
This inactivates adenylyl cyclase → no more cAMP formed
Enzymes in the cytosol degrade cAMP → stops the activation of more protein kinase A molecules
Phosphatases remove phosphate groups from activated proteins → this inactivates the proteins
Receptor Kinases
A receptor kinase becomes active when ligand binds
The receptors associate into dimers → dimerization
This results in the phosphorylation of another protein → transmits the signal from outside the cell to inside the cell
General Examples of Receptor Kinases
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
We will examine this pathway
