MCB 8: Cell Signalling

Question 1

Why do cells need to communicate with each other?

Answer 1

• physiological processes, such as visual, auditory processing or homeostasis, require cellular communication
• cells need to interpret many different signals from other cells, in order to coordinate their behaviours

Question 2

Where can cells receive information from?

Answer 2

• the extracellular matrix
• soluble factors from the extracellular fluid
• adjacent cells

Question 3

Why is cell signalling crucial for cells?

Answer 3

• cells need multiple signals just for them to survive
• some include signals to grow and divide, or to differentiate
• if cells are deprived of signals, most undergo apoptosis

Question 4

What types of cell signalling exist?

Answer 4

Endocrine Signalling:

• the signalling molecule is usually a hormone
• they are secreted molecules from distant sites of the body
• they travel through the bloodstream to a distant target cell
• endocrine cells produce these hormones

Paracrine Signalling:

• when a hormone (or another signalling molecule) is released from the cell it was produced from into the extracellular fluid
• usually when a hormone is used in neighbouring cells

Autocrine signalling:

• when the signalling molecule acts on the same cell

Synaptic Signalling:

• nerve signals are transmitted electrically along a nerve axon
• when it reaches the nerve terminal, it causes the release of neurotransmitters onto adjacent target cells
• conversion of an electrical signal to chemical

Contact-dependent Signalling (or called juxtacrine signalling):

• a cell surface-bound signalling molecule binds to a receptor on an adjacent cell

Question 5

In the immune system, cell surface receptors on antigen-presenting cells interact with cell surface receptors on T cells. What type of signalling is this?

Answer 5

• contact-dependent

Question 6

What is signal transduction?

Answer 6

• this is the process of signal conversion in cells
• target cells convert an extracellular signalling molecule into an intracellular signalling molecule that alters cell behaviour

Question 7

What are signalling and target cells?

Answer 7

• a signalling cell is the cell that produces the extracellular signal molecule
• a target cell is one that detects the signalling molecule
• most cells produce and receive signals

Question 8

What are the three strategies cells use to transfer information across the cell membrane?

Answer 8

• passive diffusion
• gated channels
• transmembrane receptors

Question 9

Describe how passive diffusion allows cells to transfer

Answer 9

• only certain molecules are able to diffuse: lipid-soluble hormones or permeable gas
• once they are inside the cell, they will elicit a change in the cell’s behaviour

Question 10

Describe how gated channels allows the transfer of information across the cell membrane

Answer 10

• they transfer solutes (most ions) across the membrane
• they can be closed or opened in response to a specific signal

Question 11

Describe how transmembrane receptors allow the transfer of information across the cell membrane

Answer 11

• these transmembrane proteins have a ligand-binding domain on the extracellular region and one or more transmembrane segments
• the intracellular part couples to signalling effector proteins inside the cell

Question 12

What are receptors?

Answer 12

• receptors are the protein with which the signalling molecule interact first with on a target cell
• receptors recognise and respond specifically to the signalling molecule
• each receptor usually only responds to one type of signal
• there are two types of receptors:
• cell surface receptors
• intracellular receptors

Question 13

What are cell surface receptors?

Answer 13

• usually a protein that spans the cell membrane and has parts that stick out of the cell and parts in the cytosol
• extracellular signalling molecules bind to the extracellular part
• the intracellular part passes on the message in the form of an intracellular signalling molecule

Question 14

What are intracellular receptors?

Answer 14

• only molecules that are small and hydrophobic enough to pass through the plasma membrane react with intracellular receptors
• the signalling molecule passes directly through the cell membrane and interacts with a receptor molecule located inside the cell

Question 15

How can the same signalling molecule induce different responses in different target cells? Give an example

Answer 15

• even if they have a similar cell-surface receptor, they differ in the intracellular effector proteins and transduce a different signal
• or the molecule binds to a different receptor in the first place, so the signal is different
• acetylcholine can:
• decrease heart rate in heart pacemaker cells
• increase secretion in salivary gland cells
• cause muscle contraction in skeletal muscle cells

Question 16

What are signalling cascades/pathways?

Answer 16

• a series of events triggered by a signalling molecule binding to its receptor
• the outcome is a change in cellular behaviour

Question 17

Explain how signalling pathways work

Answer 17

• signalling cascades always starts with an extracellular signalling molecule binding to the extracellular region of its receptor
• then the primary step of signal transduction occurs: this is thereceptor relaying the signal to the inside of the cell
• the signal is relayed onto a series of intracellular signalling molecules
• sometimes one molecule activates the next molecule in a pathway, or generates a new molecule in the pathway
• this goes on until it hits an effector protein
• they could be a metabolic enzyme, a cytoskeletal protein or a transcriptional regular for example
• these trigger responses in the cells

Question 18

How can signalling cascades modify the incoming signal and how can these explain the key functions of the signalling cascade?

Answer 18

• a scaffold protein holds several intracellular molecules together so that they can be activated in a particular cellular location with greater speed
• one of the key functions of signalling pathways is to relay a signal, so it can be spread throughout the cell
• another key function is to amplify the signal
• one receptor can only activate one enzyme, but the enzyme may be able to generate many different molecules as its product at any given time
• this way one molecule of receptor and enzyme can generate many intracellular signalling molecules, often messenger molecules
• these can induce a large intracellular response
• another function is to integrate signal
• at any given time, cells can have many different signalling pathways that are active
• signals can be integrated from more than one pathway before they can be relayed onward
• the change of behaviour the cell actually performs depends on how many different pathways are active and how these different pathways are regulated

Question 19

What are molecular switches?

Answer 19

• these are intercellular signalling proteins that can convert from an inactive to active state upon receiving a signal
• once activated, they can stimulate other proteins in the pathway
• they persist in the active state until some other process switches them off

Question 20

What two classes of molecular switch proteins are there?

Answer 20

• regulation by phosphorylation
• carried out by protein kinases
• regulation by G proteins
• also known as GTP-binding proteins

Question 21

Describe how molecular switch proteins are switched on or off by phosphorylation

Answer 21

• molecular switch proteins can be activated by adding a phosphate group
• the phosphate group is added covalently by protein kinase
• they can be inactivated by the removal of the phosphate
• taken off by protein phosphatase

Question 22

Describe what happens chemically when phosphorylation occurs

Answer 22

• phosphate from ATP is transferred to the protein to form a phosphoester
• proteins can be phosphorylated on serine, threonine and tyrosine residues

Question 23

Describe signalling by GTP-binding proteins

Answer 23

• G proteins are activated when they exchange their bound GDP for a molecule of GTP
• GDP is released from the G proteins and the G protein binds to GTP
• once activated by GTP, the proteins have intrinsic GTP-hydrolysing (GTPase) activity
• they switch themselves off by hydrolysing their bound GTP to GDP

Question 24

What are adaptor proteins?

Answer 24

• adaptor proteins contain protein domains that are important in molecular recognition
• they bind proteins containing particular recognition motifs and bring proteins together in space functioning like a molecular bridge
• it is a smaller protein so usually binds two proteins together

Question 25

What are the different receptor classes?

Answer 25

• ion-channel linked receptor:
• the signal molecule binds to the receptor, which opens up a permeable pore that traverses the membrane
• G protein couple receptor:
• the signal molecule binds to the outside of the G protein-coupled receptor (GPCR)
• this leads to activation of an intracellular G protein
• Enzyme-linked receptor:
• the signal molecule binds to the receptor
• this often dimerises the receptor, leading to the activation of an intracellular enzyme that is linked to the receptor
• Intracellular receptor:
• a membrane-permeable signal molecule binds to an intracellular receptor
• this drives gene expression in the nucleus

Question 26

Describe G-proteins and GPCR

Answer 26

• GPCR can switch between active and inactive states depending on whether they are bound to GTP or GDP
• They are activated by exchanging a GDP molecule for a molecule of GTP.
• They can inactivate themselves by their GTP-ase mechanism used to hydrolyse the GTP to GDP.
• G-protein coupled receptors are membrane proteins with 7 transmembrane regions and an extracellular ligand-binding site that produce fast and reversible responses
• they are encoded for by the largest family of genes and are involved in many physiological and pathological processes.
• 30% of all modern drugs use GPCRs as their targets.
• Different ligands (signalling molecules) bind to different GPCRs.
• GPCRs are associated with membrane bound G-proteins, found on the underside of the plasma membrane.
• When activated by a ligand binding, the GPCR changes conformation and activates the G-protein which can then undergo its own conformational changes.
• G-proteins are made up of 3 subunits (alpha, beta, and gamma) and when activated, it breaks up into the a-subunit and the beta-gamma complex.
• The alpha-subunit exchanges its GDP for a GTP molecule and binds to its target protein (enzyme).
• Upon GTP-hydrolysis the target protein is activated and once the G-protein is inactive, it can reform its heterotrimeric state with the beta-gamma complex and re-associate with a GPCR.
• In the case of ion channels, the beta-gamma complex binds to the channel and leads to the opening the pore allowing influx/outflow of ions.
• Once the a-subunit hydrolyses its GTP, the G-protein heterotrimerises and the ion channel is closed.
• The activation of enzymes, however, is caused by the binding of the a-subunit bound to GTP with the enzyme leading to the activation intracellular secondary messengers which amplify the signal.

Question 27

Describe enzyme-linked receptors

Answer 27

• Enzyme-linked receptors such as Tyrosine Kinase (RTK) are single-span membrane proteins which have either catalytic activity of their own, or an associated enzyme
• Many are responsible for signalling growth / proliferation / division / survival of cells and disorders in these may result in cancer.
• ELRs are the target of many cancer drugs but are slow acting and require many intracellular transduction steps to lead to a change in gene expression.
• Ligand binding on the extracellular receptor causes dimerisation of the receptors, bringing the intracellular catalytic domains closer together and activates it.
• In the case of RTK, both subunits phosphorylate each other’s tyrosine residues, and each phosphorylated site recruits a different adaptor protein.
• The adaptor proteins are activated (could be by phosphorylation) and recruit other GEF (guanine nucleotide exchange factors) proteins to activate a G-protein.
• The G-protein can then activate a phosphorylation cascade of protein kinases to eventually activate various kinases or gene regulatory proteins.

Question 28

Go into detail on G-protein coupled receptors and enzyme-linked receptors

Answer 28

• Find the ppt slides in Goodnotes

Question 29

How does an intracellular receptor function?

Answer 29

• signalling starts with the signalling molecule binding to its receptor
• In this case, a steroid hormone (cortisol, produced in adrenal glands in response to stress), crosses the plasma membrane and binds to a so-called nuclear receptor located in the cytosol.
• The complex of cortisol and its receptor then enters the nucleus via nuclear pores.
• The receptor part is active and can bind to specific gene regulatory sequences, which activates transcription.

Question 30

How do ion channels function as signalling receptors?

Answer 30

• See MCB 6 for detail
• Ion channels open or close a pore to allow the flow of certain ions across the plasma membrane.
• This causes the generation of an electric current and thus we can say that these receptors convert chemical signals into electric signals
• called signal transdunction
  1. First the signalling molecules bind to the receptor
  2. This causes conformational changes, opening the channel pore
  3. Ions can now flow across the membrane depending on their respective electrochemical gradients
• These ion channels do not bind nuclear pore complex components and can transmit signals quickly across the membrane.

Question 31

Phosphorylation is a reaction that participates in cell signalling in which way?

Answer 31

Question 32

Cortisol binds to a receptor that resides in the cytosol in the unbound state. What can you conclude from this statement?

Answer 32

Question 33

Ion-channel linked receptors are able to…

Answer 33