Lecture 8 - Cell communication II - Intracellular signalling Flashcards
Chemical classifications of hormones
Peptides = from three amino acids to large proteins Amines = derivatives of tyrosine (amino acid) Steroids = synthesised from cholesterol
Intracellular receptors
For steroids and thyroid hormones
To work on a intracellular receptor, the signal molecule has to be able to get inside the cell which means it either has to be able to diffuse across the membrane or there needs to be some sort of transport system in the membrane that will capture the molecule and put it in the cell (channel or transporter etc)
Lipophilic/hydrophobic so can freely diffuse across membrane and if one of the membranes it diffuses across happens to be a cell that expresses that receptor for that hormone then you will get a response for that hormone
Steroid hormone receptors
Steroid hormone diffuses across the cellular membrane and typically the most common place to find the steroid receptor is in the cytoplasm of the cell but this is not necessarily true for every cell
The steroid binds to the receptor which forms a complex and this complex then translocates into the nucleus and activates gene transcription and this generates proteins which may be the primary response of the cell or they might also be the generation of proteins that are transcription factors themselves
Some steroid hormones can be nuclear or cytoplasmic, if in cytoplasm it can move into the nucleus after steroid binding
Steroid hormone-receptor complex binds to DNA
Thyroid signalling
Tri-iodothyronine(T3) and thyroxine (T4) - these are iodinated hormones, T3 has 3 iodines and T4 has 4 iodines, T3 is more potent than T4
Transport of it across the membrane - most of it gets through by simple diffusion and then there are special transporters that enhances how much you get in by a small amount
Once inside, the T4 is often converted into T3 and this then binds to the thyroid protein receptor which is a nuclear receptor and has a cofactor of a retinold X receptor (RXR) so the complex is comprised of 3 units (THR, cofactor and T3) and these things together for the active transcription factor which changes gene transcription and essentially increases metabolism and has various effects on various different cells
Hyperthyroidism tends to be people who have highly active metabolisms and are very skinny, hypothyroidism means that there is lower energy expenditures therefore these people tend to be heavier and have more problems with their weight
Cell surface receptors
Lipophobic/hydrophilic receptors, cannot enter the cell therefore have to work on receptors on the cell surface
Surface receptors then change some sort of signalling mechanism within the cell so what happens is that the hormone binds to the receptor and activates it and the second thing that happens is that intracellular machinery gets activated so the intracellular machinery is the secondary messenger system
Ligand gated ion channels
Cell surface receptor example
Ionotropic receptor
Ligand comes and binds to open the channel and once open ions can flow in
G protein coupled receptors - Gs and Gi
Gs = stimulatory g protein
Gi= inhibitory g protein
Stimulatory and inhibitory do not refer to the cells response, it refers to what the secondary messenger’s system response is
Gs stimulates activity of the secondary messenger system and Gi reduces/inhibits activity of the secondary messenger system (this does not mean that the cell itself is inhibited or stimulated because you might stimulate the secondary messenger system to do something like make more potassium channels which tend to make electrical cells less excitable)
When the receptor us activated, if they are not already associated with a G protein then they certainly are now
Activate GPCR which is coupled to a G protein is made up of alpha, beta and gamma subunits. This coupling/ chemical interaction knocks off a GDP from the g protein complex and lets GTP bind which is an energy substrate molecule which splits the G alpha and the Gbeta and Ggamma so they fall off the receptor (split from each other) and then each of these can activate downstream processes inside the cell and the one best characterised and seems to be the most consistent between all cells is G alpha and this is the one that stimulatory and inhibitory refers to
The G alpha subunit activates adenylyl cyclase which converts ATP into cyclicAMP and you often see cyclic AMP mentioned as the second messenger for this system as it is the messenger that leaves the membrane and enters the cell and this then activates protein kinase A (PKA) and the activated PKA then can activate CREB which is cyclicAMP response element binding protein which binds on to the DNA and causes gene transcription and the making of protein
Gs
Stimulatory G protein
Gi
Inhibitory G protein
G protein coupled receptors - Gq
Q originally stood for queer because it did not act through cyclic AMP (so Gs and Gi involve cAMP production and Gq does something different)
Different G protein complex but the same fundamental type of complex just with a different process
G protein complex with alpha, beta and gamma subunits bound and this diagram shows that it is associated with the receptor before
Receptor binding causes GDP to be knocked off and GTP to bind and the alpha and the beta/gamma subunits separate and the alpha subunit in this case activates phospholipase C which generates inositol triphosphate which leaves the membrane therefore it is called the second messenger and diacylglycerol also leaves the membrane so it is also considered a second messenger
IP3 acts on IP3 receptors on the endoplasmic reticulum and this allows for the opening of these ligand gated channels which allows for calcium release and then calcium goes on to stimulate things that are calcium dependent
Diacylglycerol activates protein kinase C which phosphorylates other molecules (e.g. the protein in the diagram has phosphate added and now it can cause a response)
Enzyme linked receptors - receptor tyrosine kinases
Receptors that have a tyrosine kinase within their structure/part of the receptor
Tyrosine kinase phosphorylates tyrosine, not tyrosine that are alone in the cell, tyrosines that are on proteins and when phosphorylated it typically activates the proteins
Enzyme linked receptors
When signal molecule binds, it binds to the receptor and causes them to come together so they stabilise a complex (cause it to become an active catalyst)
The stabilisation of this complex allows interactions in the intracellular portion of the receptor that then activates enzymes (other proteins) in the cell so the key think here is that it is the phosphorylation of the proteins which are doing something inside of the cell
Enzyme lined receptors - tyrosine kinase-associated receptors
Not the same as receptor tyrosine kinases and the clue is in the association- it is where the tyrosine kinase is associated
In the diagram, the first messenger/hormone/neurotransmitter is binding to the receptor in the membrane and the JAK kinase is another protein that is stuck on the receptor
JAK is part of the JAK STAT pathway and typically the response of JAK STAT pathways is that you end up with gene transcription as well
Janus kinase is associated with the receptor
Regulated intramembrane proteolysis
Proteolysis = protein breakdown
Metalloproteins (metallic, protein, breaking it down)
Proteinase= same as protease
Signal molecule binding which allows for the cleavage essentially of the protein that it binds to
Then part of this molecule then becomes the second messenger which travels into the cell through translocation into the nucleus and acts as a transcription factor and changes the transcription of genes and eventually new proteins might get made which can either increase or decrease the output of the cell
Eicosanoid receptors
Similar process to regulated intramembrane proteolysis but this time it is not protein that are broken down it is the lipids themselves
Activate receptor which activates phospholipase A2 (phospholipids are broken down)
So the membrane phospholipids are broken down into arachidonic acid which can then go down the cyclooxygenase pathway which produces among other things prostaglandins which are involved in maintaining vascular tone and is absolutely essential for childbirth as it is involved in uterine contractions
