Cell Communication (Lecture 2)

All 4 cellular communications rely on the signalling molecules:

peptides
steroids
proteins
hormones
neurotransmitter

The 4 super families that group the receptors based on their structure -

• Ligand gated ion channels
• G protein coupled receptors
• Kinase-linked receptors 
• Nuclear receptors

The 4 receptor classes or major super families basically is determined by their structure and this detrmines their structure.

Ion Channel:

• A macromolecules that is composed of different protein subunits that surounds an ion channel
• A signalling molecule then comes along and binds to it based on its structure
• Really simple, really direct

More complex than the ion channel:

• dimorisation of 2 monomers that come together
• then there is exposure of the tyrosin residues that then need to be phospohoralated
• relay proteins then come in

These are the receptors that will be activated by signalling:

• Ligand-gated ion channels
• G protein coupled receptors
• Kinase-linked receptors
• nuclear receptors

Main characteristic - composed of multiple protein sub-units.

They come together to form an ion channel, the way they move apart lets ions into the cell. 

It is a very quick and a direct response the opening of the ion channel.

Time Scale - milliseconds as they are super fast

These types of receptors are usually found on muscle cells, neuromuscular junction, expressed in the brain, they facillitat the fast cellular communication...an example would be the nicotinic receptor.

These are abundant in the body

they facilitiate many physiological process (we are going to discuss in terms of the sympathetic response (fight or flight))

Adrenaline bind to adreal receptors. 

G protein coupled receptors work by the activation of g proteins. the work horse protein that interacts with effect moleucles . these could be enzymes, ajacent ion channels. so the g proteins interact with these effectors. by doing so they can stimulate a cellular signallilng pathway or they could inhibit depending on the type of coupling the g protein has to the receptor.

Timescale - These have a longer duration signalling pathway, seconds, a bit longer as they have phosphoralation and many enzymatic reactions, changes in excitability.

Sometimes reffered to as enzyme coupled receptors.

2 monomers come together and dimorise (more complex) 

Initiation of varieous cell signalling pathways.

They are involed in processe in growth and metabolism, processes that take a long time to develop usually have these receptors. 

Generally bound to steroid hormones. this is logical as they have a cholestorol backbone.

This makes them lipophillic which means they  can cross the plasma membrane themselves.

They then bind to nuclear recpeotrs which are then activated they then bind to a DNA binding domain and they initiate the changes in gene expression.

Timescale - generally in hours maybe even days for these celluloar changes to occur.

Generally are composed of different sub units. Youll find that subunit composition has different physiological and pharmeological properties.

The subunits basically suround a cenrtally located ion channel. when the receptor is not bound by the signalling molecule (could be a hormone or drug) - drug very genrally tern it changes physicoligcal function in some specific way. (very genreic term). 

• it contains a neurotransimiiter / hormone that binds and activates the ligand gated ion channel 
• to do this its very similar to lock and key
• the signalling molecules has a specific chemical composition to it this allows it to fit to the specific binding site.
• signalling molecules matches the receptor then it initiates a conformational change. This generally involves the protein subunits to come apart a bit to let the ions travel through.
• the ions going into the cell is a bio electrical current. sodium ions going into the cell (nicotinic acetycholine receptor)
• very quick duration (occurs in milliseconds)

• there is 5 protein sub units that suround a centraly located ion channel bound by nicotic which is an exoginist drug  or its bound by acetylcholine which is a hormone for a neurotransmitter
• then it gets activated and the ion channel widens to allow sodium potassium and sometimes  calcium into the cell
• this is a concentration gradiet and is very fast. this is anm excitatory response.
• if you look in terms of a synapse you have collenergic neuromission.

• release of acetycholine and it binds to the nicotinic acetylcholine receptors
• this causes them to open up their ion channels
• this allows sodium ions to travel in as they have a postivie charge and this is an excitatory
• if enough of these receptors are activated there is going to be enough of the excitation to trigger an action potential

3 main types of signalling mechanisms for g protein coupled receptors. all share a common signalling molecule.

B2 adrenreceptor:

• B2 are coupled to the alpha  subunit.
• beta 2 adrenrecptor is expressed mainly in the smooth muscle of the bronchi in the lungs. beta 1 is in the heart.
• the beta 2 adreorecptor controls the dilation of the bronchi. 
• adrenaline binds to the beta 2 adrenareceptor. it activates the receptor as an agonist. it causes a  conformational change in the structure when it is activated
• this allows for the g protein to bind. the g proteins are coupled with gdp when they are inactive.
• now the g protein is bound to the recpetor the g protein alpha subunit changes. gtp exchanges with the gdp. so gtp is now bound to the alpha subunit. it charges it up.
• it then goes to the ezyme that is nearby. G alpha s stimulates the enzyme (adenocyclase.) 
• adenocyclase then converts what is activated atp to cyclic amp. 
• this then initiates PKA (protein kinases A) which then inhibites MLCK
• this resultes in bronci dilation (smooth muscle relax)
• the GTP breaks up , hydrolises and becomes GDP again. this switchews off the adenocyclase.
• adrenaline also comes away from the receptor - this changes the confirmation back to how it was at the start awaiting the next signalling molecules for the process to start again.

• the same thing occurs but you get an inhibition of adenocylcase.
• adenyl cyclase is already working, now it will be switched off by the activation of the alpha 2 adren receptors.
• adrenline comes in, causes a confirmational change of the alpha 2 adreoceptor which then allows for the alpha subunit of the g portein to latch on and couple. 
• once its coupled it its activated by the GDP going away and the GTP joining on and charging up.
• This inhibits adenylcyclase, switches it off. 
• This isnt the only thing that the G protein coupled receptors can do:

Beta gamma subunits exert a cellular effect by interacting with adjacent ion channels (opening up ion channels - allows for K ions to go in or out) 

This is the way the parasympathetic nervous system switches off digestion. 

the hydrolisation of GTP cuases the system to be switched off and GDP returns.

The G alpha Q receptors stimulates an enzyme called phospholypase C.

This type of receptor you generally get some sort of excitation

• once again the basic mechanics are the same:
• adrenaline binds to the alpha 1 adrenrecptor that causes a confirmation change that allows for the G alpha Q subunit to bind to the receptor.
• this causes for an exchange of the GDP for GTP which charges it up and then stimulates phosphlypase C which then converts PIP2 to DAG.
• this causes the intercellular calcium stores to be released and cause vasorewstriciton.
• you get a hydrolisation of GTP which switches it off - back to GDP.

Adrenaline binds to all of these but will initaite different cellular effects and that then initiates different physiological effects.

2 things to think about: the receptor itself and the signalling pathway

A good example is adrenaline:

Asthma:

• Adrenaline - it would open airways but full sympathetic response (higher heart rate ect by binding to both the beta 1 and beta 2 receptors)
• Salbutamol - binds/activates only the beta 2 adrenoceptors which gives the desired effect of bronchodilation.

Also called the enzyme -coupled receptors
These are involved in metabolism and growth

Example : Insulin

• Insulin will come in and bind to the monomers which causes the monomers to come together. 
• This exposes tyrosine residues, these are easily phosphoralated by ATP. (Noramlly ATP can be found close by the receptors.
• When the tyrosine residues are phosphoralated on the intracellular side on these types of receptors.
• this is critical to the type of signalling that occurs. 
• Relay proteins hang around waiting for the tyrosine residues to be phosphralated. These can then attach and they themselves then are phosphralated and the result is divergent cellular resonses. Different relay proteins result in different types of signalling
• Due to the many divergent pathways this is why it takes hours/ days rather than seconds.

• These enter the cell as they are lipophillic and bind to the steroid receptor.
• That shuttles it into the nucleaus
• in the nucleus there are DNA binding domains which then initiates a change in gene transcription
• This is an activated hormone receptor complex that forms within the celland switches on the genetic activation resulting in the expression of various types of proteins
• these could be enzymes that could further cause changes in the intracellular signalling or protein subunits in terms of the ligand gated ion channels
• this is a very long term effects. These types of recepotrs are invovled in growth and metabolism

examples are estrogen and testosterone.

Molecular Biology of the Cell, Alberts et al. 6th edition - chapter 11 p627-628, chapter 15, p818-823, p851-852, p874-877