21. cell signalling

How do cells in communicate

By releasing chemical messages targeted for cells that are not immediately adjacent to them.

What are the two types of cell communication and their description

Direct communication: involves physical contact between interacting cells

Indirect communication: involves extracellular chemical messengers or signal molecules that bind to receptors

What are the 3 steps of cell signalling? (Ross stops chandler)

1. Reception

2. Signal Transduction

3. Cellular response

What is a ligand

A signal molecule that binds specifically to another molecule usually a receptor. Aka first messenger

What is the first messenger?

Ligand

What is a receptor

A protein that binds and transduces the message of the signal molecules into a cellular response

What is signal transduction

A series of steps which signals are conveyed into the target cell where they are transformed into a cellular response

Outline the process of reception (ligand receptor interaction)

• A specific ligand binds to the extracellular ligand-binding site of the specific receptor

• Ligand binding causes the intercellular domain of the receptor protein to undergo change in conformation (G: conformational change directly activates the receptor K: dimerisation of two or more receptor subunits)

• Change in conformation of intracellular domain activates the receptor protein, enabling it to interact with other cellular molecules (e.g. relay protein)

Why is ligand receptor interaction specific?

Ligand is complementary in conformation and charge to extracellular ligand binding site of the receptor. hence specific ligand can bind to ligand binding site for a particular type of receptor.

What are the two different types of receptors?

(Hint: location)

Cell surface receptors and intracellular receptors

Describe cell surface receptors

• located on CSM

• Bind to large polar hydrophilic signal molecules that

• Cannot diffuse readily across the hydrophobic core of phospholipid bilayer

• 3 domains: extracellular (LBS), trans membrane (embeds receptor protein in the membrane), intracellular (undergoes conformation change upon ligand binding)

What is the effect of receptor protein being activated

It can interact with other cellular molecules, and other proteins known as relay proteins can be activated by the receptor.

What are the 3 features of signal transduction stage (S→F)

1. Multiple steps (S)

• activated receptor activated another relay protein and so on, until final protein produces a cellular response is activated

• Activity of relay proteins can be regulated via phosphorylation/dephosphorylation

• (F) allows multiple checkpoints for regulation, as cellular response produced can be controlled at each step

1. Phosphorylation cascade

• sequence of events where one enzyme phosphorylation another, causing a chain reaction, leading to phosphorylation of thousands of proteins

• Phosphorylation/dephosphorylation modifies it

1. Signal amplification

• number of activated molecules at each step of signal transduction pathway increases

What are second messengers

Small non protein, water soluble molecules or ions.

→ small and water soluble → spread rapidly throughout cell by diffusion → function effectively in cytoplasm

What is the function of second messengers

Help activate cellular proteins in cytosol

Give an example of second messengers

• Cyclic adenosine monophosphate (cAMP)

• Ca2+

• Inositol triphosphate IP3

• Diacylglycerol (DAG)

Describe the activity of cAMP

• Signal molecule (first messenger) activates a GPCR, which activates a specific G protein

• In turn, the G protein binds and activates adenylyl Cyclase, which catalyses the conversion of ATP to cAMP

• CAMP diffuses through cytosol and binds to another protein to activate it.

• Once function is completed, cAMP will be converted to adenosine monophosphate AMP to ensure cellular response does not persist permanently.

Phosphorylation and dephosphorylation are types of __ That help regulated protein functions

Post-translational modifications

What enzyme carries out protein phosphorylation and what does it do

Kinase: adds phosphate groups from ATP to the protein

What enzyme carries our protein dephosphorylation

Phosphatase: removed phosphate group from proteins by hydrolysis

What are most of the relay molecules

Protein kinases

How is signal transduction pathway switched off

In the absence of extracellular signal, it is switched off by protein phosphatases , where phosphate group is removed from active protein kinases and relay proteins, thereby inactivating them. This shuts down the signalling pathway and cellular response.

What is signal amplification

A large number of intracellular mediator is produced from a relatively small number of extracellular signals.

Explain the 4 points of signal amplification

• a small number of extracellular signal molecules activate large number of intracellular molecules + produce a large cellular response in signal transduction pathway

• 1 signalling molecule → 10^8 final products

• Protein kinases (relay proteins) when activated, catalysed the phosphorylation of several other specific proteins in the next step, thus, activating these proteins.

• Protein phosphatase terminate the responses initiated by receptor activation of protein kinases

Does every step in transduction pathway result in signal amplification?

Only steps involving the production of many more activated molecules will amplify the signal.

What is the basis of signal amplification?

• at each step, if one molecule can activate many molecules, it produces a large amount of the final product

• This allows signal transduction to amplify the signal even with very little quantity of signal molecules/receptors at the start, thus resulting in a large cellular response

Why is signal amplification required?

There may not be enough receptors to yield the appropriate cellular response needed, so signal amplification helps to increase the magnitude of the signal from the first messenger to elicit an appropriate cellular response of sufficient magnitude.

What are 3 types of cellular response (GMC)

1. Regulation of gene expression

2. Regulation of metabolic pathways

3. Changes in cytoskeleton

Explain specificity of cell signalling (2)

1. Diff cell types can have diff responses to the same signal

2. Same cells can have the same response to diff signals

Give an example that illustrates diff cell types can have diff responses to the same signal

• liver cells: insulin increases permeability of glucose and stimulate conversion of glucose to glycogen

• Adipose cells: insulin inhibit breakdown of triglycerides

Give an example that illustrates same cells can types can have same response to different signal

• diff signals: glucagon and adrenaline

• Liver cells stimulated to mobilise glucose

• To stimulate breakdown and inhibit the synthesis of glycogen

Why is it that even though ligand and receptor may be the same, different responses may be elicited from different cells?

In diff kinds of cells, different sets of genes are expressed thus resulting in the presence of diff collections of relay molecules and signal pathways in dif cells.

What are the 2 points where cellular response can be terminated?

1. Reception (step 1)

2. During signal transduction pathway (step 2)

Explain how cellular response is terminated at reception

• extracellular ligand can be degraded by enzymes in the extracellular space

• Simultaneously, endocytosis of ligand-receptor complexes at CSM prevents signal transduction from continuing

• Removal of bound ligand after cellular stops signal transduction from continue permanently and preventing excessive cellular response

Explain cellular response termination during signal transduction pathway

• increased activity of phosphatases functions to dephosphorylate relay proteins, inactivating them and preventing them from eliciting cellular response needed

• OR produce inhibitors that bind to ligand receptor complexes at CSM or any intracellular relay proteins in the transduction pathway to prevent transduction of signal

What are the 5 advantages of signal transduction

1. Facilitates signal amplification

2. One ligand/extracellular signal molecules can trigger signal transduction pathway to elicit different cellular response

3. Provides multiple checkpoints for regulation

4. Ensures specificity because a specific ligand binds to a specific receptor to elicit a specific cellular response via specific pathway for a specific cell type.

5. An extracellular signal is transducer into the cell to activate genes in nucleus upon binding to cell surface receptor without the need to move into nucleus

What are the 3 main types of cell surface receptors

1. G protein coupled receptor (GPCR) e.g. glucagon receptor

2. Enzymatic receptor e.g. receptor tyrosine kinase

3. Ligand gated ion channels (FYI)

What are the 3 components of G protein system

1. GPCR

2. G protein

3. Another relay proteins

What is the structure of GPCR

• cell surface receptor

• 7 alpha helices spanning the membrane (7 transmembrane domains)

• Extracellular ligand binding site

• Portion of intracellular domain that interacts with a G protein

What is the structure of G protein

• found on cytoplasmic side of membrane

• Protein complex made of 3 subunits: alpha, beta and gamma subunits

• Alpha subunit: GTP-binding protein

• Alternates between 2 states: inactive state is when bound to GDP, active state is when bound to GTP

What are examples of GPCR

Glucagon and adrenaline

Describe the 4 step mechanism of G protein

1. G protein is in inactive form: without extracellular signal, all 3 proteins (GPCR, G protein, enzyme) are in inactive state and G protein is bound to GDP molecule

2. G protein is activated: signal molecule binds to receptor, triggers conformational change in intracellular domain of receptor that it binds to inactive G protein Alternates between→ GTP displaces GDP on inactive G protein, activating it

3. Active G protein activates another protein: it dissociates from receptor and moves along the cytosolic side of CSM, G protein binds and activates the next enzyme in the pathway → adenylyl cyclase is activated and catalysed conversation of ATP → cAMP → difffuses within cytosol to. Bind and activate downstream relay proteins in

4. G protein system returns to inactive form: G protein have intrinsic GTPase activity which catalyses hydrolysis of GTP to GDP → G protein dissociates away from enzyme and available for reuse

What are receptor tyrosine kinase

Cell surface receptor that bind to extracellular ligands that also function as an enzyme

What is the structure of RTK

• an extracellular ligand binding site Portion

• 1 Transmembrane domain (1 alpha helix spanning the membrane)

• Intracellular domain containing several tyrosine residues

• Tyrosine kinase is the part that extends into the cytoplasm and functions as an enzyme which phosphorylates specific tyrosine residues

• Have intrinsic kinase activity: add phosphate grp from ATP to tyrosine residues of relay proteins

Describe the mechanism of RTKs

1. Reception and initiation of transduction

• binding does not cause enough conformation change to activate cytoplasmic side of protein directly, instead does through dimerisation then cross phosphorylation of subunits → activated phosphorylated receptor dimer can be recognised by specific relay proteins

2. Signal transduction

• relay proteins recognise and bind to specific phosphorylated tyrosine resides of the intracellular receptor domain EITHER → conformational change → activated OR → phosphorylated by tyrosine kinase

• Each activated RTK dimer activates more diff intracellular relay proteins simultaneously → triggers multiple signal transduction pathways → elicit multiple cellular responses

• Specialised for triggering more than one signal transduction pathways at once → regulate and coordinate many aspects of cell growth and reproduction

What are 2 examples of RTKs

Insulin and Epidermal growth factor

What are the 2 hormones that regulate blood glucose concentration

Insulin and glucagon