cell signalling

What is signalling?

• How cells talk to each other

What’re extracellular signal molecules?

• Proteins, peptides, amino acids, nucleotides, steroids, fatty acid derivatives, dissolved gasses

Whats endocrine signalling?

• Signals circulated through the body in the bloodstream

• Hormones produced in endocrine cells

Whats paracrine signalling?

• Signal molecules diffuse locally through extracellular fluid

• Local mediators for nearby cells (close cells talking to each other)

Whats autocrine signaling?

• Cells respond to signals they produced themselves

• Ex: cancer cells that promote their own growth

What’s neuroscience signalling?

• Fast signal with specificity to a single target cell

• Very specific about which cell it wants to signal

Whats contact dependent signalling?

• Cells make direct contact through signal and receptor molecules embedded in the plasma membrane

How selective are receptors?

• Highly selective

What do cell surface receptors do?

• Outside cell

• Bind extracellular signals

• Used for signals that are too large or hydrophilic to cross the membrane

What are intracellular receptors?

• Inside cell

• Bind signals that pass through the plasma membrane

• Used for signals that are small and hydrophobic

What happens when receptors activate intracellular signaling molecules?

• They can activate effector proteins which have an effect on cell behavior

Can one signal cause different effects in different cells? Provide an explanation if so

• Yes, based on what type of receptor it binds to

• Ex: Acetylcholine causes heart rate to decrease and causes salivary gland to release components of saliva

Explain how a cell response can be fast or slow

• Muscle contraction is fast and occurs within milliseconds

• Cell division requires hours

What happens in intracellular signaling pathways?

• Transmembrane receptors detect a signal and relay the message across the membrane to the interior of the cell which is a primary step in signals transduction

• Molecular relay race

  • Message is passed from one signaling molecule to the next

  • Final target molecule is reached

What’re components of the intracellular signaling pathway?

• Relay the signal

• Scaffolds to bring together other components

• Amplify a signal

• Integrate signals from multiple pathways

• Distribute the signal to multiple effector proteins causing the pathway to branch

• Regulate the activity of other components through feedback

  • +ve feedback enhances response

  • -ve feedback diminishes response

What’re most relay proteins and what do they do?

• Molecular Switches

• For every activation there’s an inactivation step

Explain how molecular switches do their inactivation and activation

• Through phosphorylation

• Protein kinases attach a protein to the switch protein

  • Ser-Thr kinases phosphorylation ser or the

  • Try kinase phosphorylate tyrosine

• Protein phosphate removes the phosphate

• Organized in cascades

Whats an example of molecular switches and what do they do?

• GTP binding proteins

  • Depend on whether GTP or GDP are bound to them

  • Shut themselves off with GTP-hydrolyzing activity (GTPase)

What’re the 3 types of cell surface receptors?

1. Ion channel coupled receptors

2. G protein coupled receptors

3. Enzyme couples receptors

What’re ion channel coupled receptors?

• Change permeability of the membrane to specific ions which will change the membrane potential

What’re G protein coupled receptors?

• They activate GTP-binding proteins to interact with an enzyme or ion channel to initiate an intracellular signalling cascade

• Single polypeptide chain that passes through the membrane 7 times

• Multipass transmembrane proteins

• Receptors in processes that need to happen very quickly

What’re G proteins?

• Each has 3 protein subunits (alpha, beta, gamma)

• Alpha and gamma are bound to lipid tails

• Altered receptor activates G protein by replacing GDP with GTP

• Can break apart the subunits which can relay the signal to other molecules

What happens in G protein in unstimulated and stimulated states?

• Unstimulated state: alpha subunits has a GDP bound

• Stimulated: alpha subunit has GTP bound

What does the alpha subunit have in terms of GTP hydrolysis?

• It has a GTPase (phosphatase) to hydrolyze GTP back to GDP

What does G proteins target?

• Target of bacterial disease causing toxins

• Ex: cholera

Explain control in G proteins

• Controls gated ion channels (ex: in heart pacemaker cells)

• Open channel when activating protein

• Closed when not

What enzymes do G proteins activate?

• They activate enzymes that produce small messenger molecules

• Second messengers amplify and spread the intracellular signal

Whats an example of a G protein coupled receptors?

• Adenylyl Cyclades activity

What happens in adenylyl cylase activity?

• Activation makes the secondary messenger cAMP

• AMP phosphodiesterase converts cAMP to AMP

• AMP activates cyclic AMP dependent protein kinase (PKA)

What blocks AMP phosphodiesterase?

• Caffeine blocks this enzyme which keeps the cAMP levels high in the cell

What gets activated and inactivated in adenylyl cyclase activity?

• Activation of glycogen phosphorylase which breaks down glycogen

• Inactivation of glycogen synthase

What’re the cell responses of adenylyl cyclase?

• Increased heart rate

• Glycogen breakdown

• Fat breakdown

• Cortisol secretion

What’re enzyme coupled receptors/ what they do?

• They act as enzymes or associate with enzymes inside the cell to activate intracellular signalling pathways

• Growth regulation, proliferation, differentiation, cell survival

• Slow responses

• Often lead to changes gene expression

What is the signal molecule in enzyme coupled receptors?

• A dimmer

Whats an example of enzyme coupled receptors?

• Receptor tyrosine kinases (RTKs)

What do Receptor tyrosine kinases (RTKs) Do?

• Extracellular signal causes 2 receptors to dimerize

• Intracellular tails are in close proximity which activates the kinase domains to phosphorylate each other on tyrosines

• Phosphorylate tyrosines serve as docking sites for other proteins (interaction domain on the signalling proteins)

• Signalling proteins bind the membrane and each other

• Large aggregates - biomolecular condensates

• Transmits signals along several routes simultaneously

How are Receptor tyrosine kinases (RTKs) terminated?

• Signal can be terminated when tyrosine phosphotases remove phosphate groups

• Signal can also be terminated by endocytosis and destruction of RTK cuz sometimes phosphotases can’t get to cell

Is signal transduction a linear process?

• No