Signalling

Cell Signalling Overview

• Used for sensing environmental signals and trigger a response in the cell
• The signal is often in the form of a small molecule called ligand
• The ligand binds to a receptor on the surface of the cell. This receptor often spans the membrane so that part of it that is facing the inside of the cell can transfer the signal
• The signal can be picked up by an intermediate receptor called a transducer or it can go direct to a response regulator which triggers an intracellular response
• Signals that are shared between cells are called intercellullar responses which get converted to intracellular responses within the cell

Steps to Cell Signalling

1. Synthesis of signalling molecule
2. Transport of the signalling molecule to target cell
3. Bind to a specific receptor
4. Start signal-transduction pathway (pathway of signals in the cell) to elicit a response

Ligands: The Signalling Molecule

• Trigger the signalling pathway by binding to a receptor
• Produced by a cell to be transported to the receptor

Types of Ligands

Diffusible Ligands

• Enter the cell directly by diffusion
• Small and hydrophobic
• Bind to an intracellular receptor
• Eg. Steroid hormones or certain gases like nitrogen oxide

Surface-bound Ligands

• Bind to a receptor on the cell surface
• Cannot diffuse through the membrane
• Eg. protein ligands
• Mostly small and hydrophilic

Receptors

• Bind to the ligand to activate the signal cascade that leads to the final response
• Can be in the cell (intracellular) or on the surface of the cell

Types of Receptors

Cell-surface Receptors

• Bind to small hydrophilic ligands
• Have 3 domains:
• extracellular domain that faces the outside and binds to the ligand
• hydrophobic domain that spans the membrane
• intracellular domain that faces the inside of the cell and transfers the signal inwards

Intracellular Receptors

• Bind to diffusible ligands (small, hydrophobic) such as hormones
• Can often enter the nucleus to regulate gene expression
• Features include: DNA-binding domain, ligand binding domain

Second Messengers

• The first ligand triggers the production of a second ligand to continues the pathway
• This ligand called the second messenger is produced intracellularly and binds to an intracellular receptor
• Usually a small, non-protein molecule like calcium ions (Ca2+)

Example: Cyclic AMP

G-Protein Coupled Receptors (GPCRs)

• A G protein is attached to the intracellular side of the membrane.
• They have three subunits: the alpha, beta, and gamma subunits.
• G proteins have the ability to bind GTP and GDP.
• The variety of GPCRs comes from the variety of molecules they activate.

General GPCR pathway:

1. Before the ligand binds, the G-protein is associated with its subunits, holding a GDP.
2. The signal molecule binds to the cell surface receptor.
3. Upon binding, the receptor undergoes a conformational change that activates the G-protein.
4. The G protein's alpha subunit then lets go of GDP and picks up GTP and is now active.
5. The G protein then dissociates from the GPCR and into alpha and beta-gamma subunits.
6. These subunits can go activate other proteins as a result.
7. Eventually the GTP is hydrolyzed to GDP.
8. The subunits re-associate and the cycle starts again.

Receptor Tyrosine Kinases (RTKs)

• On the extracellular side, RTKs have the receptor domain, and the enzyme domain is located on the intracellular side of the membrane.
• The enzymatic domain contains a tyrosine residue and acts as a kinase. Kinases are enzymes which transfer phosphate groups - a type of reaction which is called a phosphorylation reaction. RTKs act in dimers (pairs).
• Upon binding of the ligand (the signaling molecule), the RTK undergoes a conformational change, causing two RTKs to come together and form dimers.
• Once together, each RTK in the dimer phosphorylates the tyrosines on the other RTK. This is called cross phosphorylation.
• Once phosphorylated, the enzymatic domain acts as a docking platform for other proteins involved in signal transduction.

phospholipases hydrolyze ester bonds in glycerophospholipids converting them to fatty acids

• Circulate through the blood to targeted tissues and relay messages
• Cholesterol is the base for all animal steroids

• Phospholipids contribute to signaling through local chemical signals
• phospholipases hydrolyze ester bonds in glycerophospholipids converting them to fatty acids
• Several different phospholipases are present and they each break different bonds along the glycerol/carbon chain
• These cleaved signaling molecules are precursors of eicosanoids
• Eicosanoid signaling pathways are involved in inflammation, heat, pain, smooth muscle contraction, pregnancy and so on