NS

Lecture 8 CSF Cell Communication

Lecture Objectives

  1. Describe the overall method of cell signalling

  2. Describe, compare, and contrast the 2 major cell surface receptors (G protein coupled and ligand-gated ion channel receptors)

  3. Describe signal transduction via a phosphorylation cascade

  4. Describe the role of the 2 main secondary messengers (cAMP and Ca2+)

  5. Give examples of cellular activities as outputs of cell signalling

Overview of Cell Signaling

  • Cell signaling enables cells to communicate and respond to their environment and other cells.

  • Key signals can be chemical (hormones, growth factors) or sensory input (light, taste).

Types of Signalling

  • Paracrine Singalling - Act locally to effect nearby target cells (Fibroblast growth factor FGF)

  • Synaptic Signalling - Acts locally from cell to cell while going through the synaptic space (Acetylcholine - ACH)

  • Endocrine (hormone) SIgnalling - Acts long distance from endocrine cell into the bloodstream

3 main steps of Cell Signalling

  1. Reception

    • Signaling molecules bind to receptor proteins, causing shape/chemical changes.

  2. Transduction

    • Altered receptor activates a protein and cause a relay of changes relay molecules such as “second messengers” may be activated e.g cAMP, IP3

    • Each activated protein causes a series of changes often via phosphorylation, known as a phosphorylation cascade

  3. Response

    • The final output is a cellular response (e.g., gene expression, altered protein function).

Reception (2 main Receptors)

- Receptors for water soluble molecules are membrane bound

- Receptors for lipid soluble molecules are not membrane bound

  • G Protein-Coupled Receptors (GPCRs)

    • Transmembrane protein, GPCRs couple with G proteins and act as molecular switches - on or off depending if GDP or GTP is bound

    • Functions are development, sensory reception (vision, taste, smell)

    4 Steps:

    1. At rest receptor is unbound and G protein is bound to GDP and enzyme is in inactive state

    2. Ligand binds to receptor and binds the G protein. GTP displaces GDP, enzyme still inactive

    3. G Protein is active and releases from receptor, enzyme now activated to carry out cellular response

    4. G protein has GTPase activity meaning GDP is back on receptor and now resting state, enzyme inactive

  • Ligand-Gated Ion Channels

    • Channels contain a “gate”

    • Receptor - Molecule/protein which responds to specific ligand/signal

    • Ligand - Signalling molecule that binds specifically to another protein

    • Ion Channel - Membrane protein through which specific ions can travel

    • Ion Channel Receptor - Membrane protein where specific ions can travel in response to ligand binding

3 Steps:

  1. At rest ligand is unbound, gate is closed

  2. Ligand binds, gate opens, specific ions can flow into cell

  3. Ligand leaves, gate closes, back to resting state

Signal Transduction (Phosphorylation Cascade)

  • Protein kinases are enzymes that transfer a phosphate from ATP to another protein, typically this activates the protein - Series of protein kinases each adding a phosphate to the next kinase

  • Phosphatases are enzymes that dephosphorylate (remove the phosphate) making the protein inactive but recyclable

Role of Second Messengers in the Cascade

  • cAMP (cyclic adenosine monophosphate)

    • Acts as a second messenger, activating protein kinases (e.g., PKA).

    • Involved in GPCR signaling pathways.

  • Calcium Ions (Ca2+)

    • Used in signaling due to concentration gradients; flows from high to low concentration, activating proteins for cellular responses.

    • Calcium concentration is high in ER, outside of cell, and in mitochondrial matrix

Ca2+ and IP3 in GPCR signalling

  • Here the activated protein is Phospholipase C which then cleaves PIP2 into DAG and IP3

  • IP3 diffuses through the cytosol and binds to a gated channel in the ER

  • Calcium ions flow out of the ER down the concentration gradient and activates other proteins creating a cellular response

Cellular Responses

    • Alteration of gene expression

    • Changes in protein activity

    • Ion channel regulation

    • Organelle regulation

    • Metabolism adjustments

    • Cytoskeletal rearrangements

  • Homeostatic Regulation: Signals act temporarily to promote precise cellular functions.

Case Study: Adrenaline Function

  • Upon sensing danger (e.g., a predator), the brain signals for adrenaline release, which binds to muscle cell receptors, triggering glucose release for energy during flight.

    • Example of amplification: One adrenaline molecule can generate millions of glucose molecules through signaling pathways.

Practical Applications and Considerations

  • Understanding signaling is crucial in various fields (e.g., drug development, disease mechanisms).

  • Specific receptors (like ACE2 for COVID-19) highlight how signaling can be misused by pathogens.

Summary

  • Cell signaling is essential for cellular communication and function.

  • The complex interplay of receptors, signals, and pathways ensures specific responses that are critical for maintaining life and responding to changes in the environment.

  • Receptors are specific, and only certain target receptors will interact with the signal/ligand

  • structure determines function

  • Response must be turned off to ensure homeostatic equilibrium