Lecture 8 Flashcards
Why do cells communicate
Cells need to be able to respond as a cell, as a part of a whole tissue, and as an organism for function - basically just think back to the levels of organisation
They respond to signals from other cells and from the environment
These signals are often chemical (but can also be sound or light - from environment)
Describe Local signalling
Signals act on nearby target cells
Examples:
Growth factors such as fibroblast growth factor - FGF1 (paracrine)
Neurotransmitters such as acetylcholine – ACh (synaptic)
Long distance signalling
Signals act from a distance
- Hormones produced by specialised cells travel via circulatory system to act on specific target cells
E.g. insulin from pancreatic beta cells to insulin receptors (tyrosine kinases) initiating a cascade which results in glucose uptake.
(this is called endocrine signalling)
What are target cells
Target cells are cells that have receptors (reminder they are proteins) which can respond to certain (e.g. chemical) messengers
Describe and name the 3 main steps of cell signalling:
Reception
Transduction
Response
Cell signalling is where a ligand is used to activate (not enter through) the protein which also activates further proteins and in doing so eventually elicits a cell response
Describe receptor
a molecule/protein which responds to a specific ligand
Describe ligand
a signalling molecule that binds specifically to another protein
Describe reception
Ligand or Signalling molecule (or First/Primary messenger) binds via the binding site to a receptor protein.
Results in shape and/or chemical state change in the receptor protein
Describe transduction:
Altered receptor (e.g. GPCR) activates another protein (always at least a few) - e.g. G protein/adenylyl cyclase)
The activated protein (often an enzyme) may cause a relay of changes
Relay molecules known as “second messengers” - eg. cAMP, IP3 - may be produced
Multiple other proteins may be activated
Each activated protein causes a series of changes, this is often via phosphorylation – known as a phosphorylation cascade
Describe response:
All of the activated proteins cause one or more functions to occur in the cell
This is where the cell actually does something
Describe receptor specificity
Receptors are very specific: only the target receptor on the target cell will interact with that signal (ligand) and use it to activate signal transduction pathways (the lock and key analogy).
We have specific receptors because of the differing 3D molecular shape of the proteins involved - structure determines function. Particular amino acids (within the protein) will have different properties which will dictate the proteins shape and also what it does (likely both relate to reception).
Specific receptors can be tricked by (evolved) viruses (e.g. ACE2 receptors in our respiratory tract can be tricked by S protein on coronavirus so the virus can enter cell)
Explain exquisite control:
Only certain cells at certain times will have particular receptors, meaning that while the signal might be widespread, the transmission of the signal occurs only where it is needed.
What are the two main types of receptors
Intracellular receptors
Membrane-bound/cell surface receptors
Describe intracellular receptors:
Ligand/Primary messenger is generally hydrophobic and/or small – lipid soluble, can enter the cell without binding to proteins
Least common method of signalling
- e.g. Testosterone, estrogen, progesterone, thyroid hormones bind to receptors within the cytoplasm and move to nucleus as a complex (many hormones go via this, especially lipid ones)
Membrane-bound/cell surface receptors: (focused on)
Primary messenger is generally hydrophilic and/or large
Most common method of signalling
eg. G Protein Coupled Receptor, Receptor Tyrosine Kinase, ligand-gated ion channel
Name three example of receptors
GPCR
Ligand gated ion channels/receptors
Extra: Receptor Tyrosine Kinase/RTK (one with rabit ears)
Describe a GPCR
Structure:
They are transmembrane proteins - has alpha helices that pass through the PM 7 times (enough hydrophobic residues must be on the protein in the fatty part of PM)
Hundred of different GPCRs exist w/ many different ligands
Functions:
Diverse functions: development, sensory receptors (vision, taste, smell).
Process:
When the signalling molecule is attached to the GPCR, there is a structural change, and the G protein can interact and become active. The G proteins swaps its GDP for GTP - GDP is DISPLACED, NOT phosphorylated
Then the activated G protein dissociates from the receptor/GPCR, and an enzyme is activated to elicit a cellular response.
Then, the G Protein has GTPase activity, promoting its release from enzyme and reverting it back to resting state (GTP loses a phosphate due to enzyme to produce GDP NOT DISPLACEMENT)
Again, G proteins are molecular switches which are either on or off depending on whether GDP or GTP is bound (GDP and GTP are similar to ATP)
GPCR’s are the target for roughly 1/3 of modern drugs
Ligand gated ion channels/receptors
Structure:
Channelling receptors that contain a gate for specific ions
Function:
Binding of ligand (e.g. neurotransmitter) at specific site on receptor elicits change in shape of protein (parts of proteins can physically move to open/close gate)
Channel opens and specific ions can pass through (e.g. Na+, k+, Ca2+, and/or Cl-)
When ligand disassociates, gate closes
Examples:
Exists in nervous system: released neurotransmitters such as acetylcholine from vesicles in axon terminals of neurons bind as ligands to ion channel receptors on target cells (e.g. muscle cells) to allow for ions to enter/propagate action potentials
Ion channel/ionotropic receptor = membrane protein through which specific ions can travel, in response to ligand binding
Ion channels may not be in receptor proteins (not 100% sure)
Describe a signal Transduction Pathway
Signals relayed from receptors to target molecules via a cascade of molecular interactions
Describe a phosphorylation cascade
Signalling molecule binds, receptor changes and eventually (e.g. via activating a prior secondary/relay molecule and therefore producing a second messenger) activates a protein called a kinase. This protein transfers of a phosphate group from ATP to the next protein which typically activates it. This process can continue for a while (if the next proteins are also kinases)
Typically result in cell response
Importantly there are phosphatases that dephosphorylate the kinases (so inactive but recyclable)
Protein kinases
Enzymes that transfer a phosphate group from ATP to another protein. Typically this activates the protein, Can also deactivate proteins but either way changes the structure and therefore function
Phosphorylation cascade is when there is a series of protein kinases each adding a phosphate to the next kinase
Phosphatases
Enzymes that dephosphorylate (remove the phosphate) rendering the protein inactive but recyclable (available for subsequent activation), as we don’t want it to stay activated. This process is as quick as the cascade, and will keep occurring while signal molecule is still there in most systems
What amino acid residues can be phosphorylated
In a given protein, not all amino acid residues can be phosphorylated, and typically serine or threonine residues are phosphorylated, meaning mutations affecting these residues could be detrimental (mean protein doesn’t function).
Describe phosphorylation
Addition of a phosphoryl group to molecule.
It is present in cell signalling pathways.
Phosphorylation is not just to do with pathways but many other proteins that need to be phosphorylated to be active/inactive as well
