Signalling pathways induced in cells - Cell Biology
What does biochemical signalling need
A signal ligand that form a complex with a receptor protein to then cause a confromational change in the receptor that generate a signal
Where are these signals released from
Contact dependent signals are able to target adjacent touching cells
Cell matrix signal are signals from the insoluble extraceullular matrix
Soluble signals are from the autocrine, paracrine and endocrine system
What are contact dependent signals
There is a physcial intercation needed between the membrane of the 2 cells
The cell must be touching for a signal to be generated and the signal is transmitted through the cell membrane via protein and lipid components in the plasma membrane
What are autocrine signals
These signals are secreted and effect the target cell itself via its own receptor, so the target site is on the same cell as the where the signal has come from
What are intracrine signals
These are produced by and stay within the target cell
Steroid hormones can act as intracrine due to their receptors in their cell
What are Paracrine Signals
These ars signals that are able to target cells in the vicintiy of the emmitting cell
Immune cells and neurtransimitters at the synapse
What are endocrine signals
These signals are able to target distant cells by producing hormones that are able to travel in the body via the circulation system
Such as Adrenaline and Thyrid hormones
Hormone binding how does it happen
There are very low levels of hormones in the blood system
This means that the hormone receptor has a greater binding affinity so stronger interaction between ligand and recepotr
Means that only a few receptors per cell
What are the external messengers molecular makeup
Can be gases, Nucleic acids, Fatty acid derivatives, Cholesterol derivatives, Amino acids, Peptides and Proteins
How does the signal moleucle determine the receptor location
Due to lipophilic molecules can enter the cell via the membranje so the receptor can be anywhere often in the cytosol
Hydrophillic molecules cant cross the plasma membrane so receptors are all on the cell surface
Thyroid hormones are hydrophobic but have carrier to bring the ligand into the cell to the receptor in the cytoplasm
What is Signal Transduction
How chemical or physical signals are transmitted though a cell as a series of molecular events
They from due to shape change of the receptor after ligand binding gives rise to signalling cascade which is a chain of biochemical events = signalling pathway
How do signalling pathways interact
They can interact with each other to form a network that allow cooridnated cellular responses
Signal transduction can alter cell growth, proliferation, metabolism, movement, secretion
What is the first messenger
Signalling molecules that reach the cell from the extracellular fluid and bind to specific receptors
What are second messengers
Substances that relay a message from plasma membrane to the cytoplasm to trigger a response due to signalling molecule cant enter the cell
How to turn off signals
Spontaeneous breakdown
Enzymatic breakdown like in ACH that broken down at the post synaptic nodule so only short effecr
Reuptake where neurotransmitters are moved back to the scereting cell to be sued again
Receptor/Ligand internalisation where they are bought into the cell following the binding so effect only 1 cell
What are examples of Lipophilic signalling
Nitric Oxide , Steroids , Thryoxine
What are examples of hydrophilic signalling
Ligand gated ion channel + G protein linked receptors, Enzyme linked receptors
What is nitric oxide signalling
NO is a non-polar local mediator
Its synthesis leads to a direct release due to being lipophilic it cant be retained in the vesicle store
It imediatly leaves synthesis site and diffuse into adjacent cells that have an NO receptor
What sre the 3 types of NO signalling
eNOS- In Blood vessel and endothelium cells
nNOS- In Neuronal cells
iNOS- Indcuible isoform in cells of the immune system
How is the NO synthesis pathway made
Made from arginine that then loses the amine group and then combine with oxygen
Leading to citruline + H2O + NO
What does eNOS do
No will diffuse directly to the smooth muscle cells to cause them to relax
Is a local regulator of blood vessel tone due to control the diamter of the blood vessel so control the blood pressure due to narrow vessel = higher blood pressure and vice versa
How does eNOS reduce blood pressure
The target for NO is Guanylate cyclase and it binds to the active site of the Guanylate Cyclase to activate it
The cGMP prodiuced then act as secondary messenger and causes muscle relaxation
How to stop the NO signalling
No will rapidly oxidize to NO3- so then cant activate the guanylate cyclase
cGMP converted to GMP by phosphodiesterase due to break phosphodiester bonds
What is Steroid signalling
Steroids are hydrophobic hormones, that are synthesized from cholesterol and cant be stored so directly released to the blood
They can diffuse into cells and bind to cytoplasmic receptors, which then causes DNA binding site to unmask and nuclear locaslisation sites on receptor
The activated receptor then travel to nucleus where DNA can bind and so can regukate gene expression
Turned off by steroid metabolism
What is Thyroxine Signalling
Thyroid hormones cant cross the cell membranes but have transporters that bring them into the cell
They then are able to diffuse into the nucleus and can act similar to steroids but their receptor already in the nucleus
Neither thryoxine or steroids have secondary messengers
What are hydrophobic Signals
Hydrophilic water soluble signal molecules cant penetrate the plasma membrane, and so need transmembrane proteins as receptors
There are 3 classes:
Ligand gated ion channels
G protein linked receptors
Enzyme linked receptors
What are Ligand gated ion channels
Needed due cell membrane is impermeable to ions
The opening of the channel can change the ion concentration at the inner side of the membrane and change the potential differance
Some ions can bind to proteins and cause a conformational change and signal transduction
Is rapid signalling and only localised
What is the Nicotinic Acetylcholine Receptor
An example of ligand gated ion channel for the signalling unit acetylcholine
The receptor is called a pentamer made of different sub-units
How is the nicotinic acetylcholine receptors made
Made of 5 polypeptides of either a2ByS or a2B3
Each polypeptide contain 4 alapha helcices with 3 being hydrophobic and touching the lipid and 1 being amphipathic and line the pores
The5 amphipathic helices produce the channel over the membrane
The a sub-unist have acetylcholine binding sites
How does the acetlycholine receptor work
Due to the acetlycholine will cause helices to rotate puling charged residues from the pore opening
Ligand binding causes transiet opening to allow cations to cross the channel
It is non-selective but mainly Na+
Negayive ion are blocked due to the size and polarity of the pores
What are G protein linked receptors
They have a 7 pass structure so cross the membrane 7 times with the N terminus always out the cell and C terminus always on the cell with large lopp between protein 5 and 6
What do the receptors associate with
Associate with the G protein compex with an alpha, beta and gamma unit in it - aby
The alpha unit hs GTP binding and GTPase
When GTP binds an actove signalling complex is formed but when converted to GDP it is inactive
Large G proteins aby link to inner plasma membrane and associate with
How do you cause signal transuction with the G protein
When inactive the G protein complex receptor is bound to heterotrimeric G protein complex
The binding of the ligand to the G proteim complex receptor causes a confromationla shape change that is transmitted to the alpha subunit of it.
Causes the alpha to release GDP in exchange for GTP
Trriger the dissocation of alpha unit from the beta and gamma dimer
This then makes both active complexes the a and the by
How do G protein dissociate into 2 signalling proteins
The alpha sub unit will leave the beta and gamma units to leave, G alpha and G beta-gamma
There are 20 forms of G alpha, 5 of G beta and 13 of G gamma
These are all different due to expression pattern, receptor binding and effects caused and is good as provdode specificity to the signals
Wat are the targets of the G alpha s subunit
Works in the B-adrenergic receptor the alpha sub-unit activate adenyl cyclase
This causes ATP to convert to cAMP
cAMP bind then to Protein Kinase A so activates it to then release catalytic sub-units
Target of the G alpha i subunit
Inactivate the adenlyl cyclase so reduces amount of cAMP
Meaning less activated Protein Kinase A
What can acetlycholine activate
Can cause the activation of 2 signalling pathways by activating Phospholipase C
Why is caclium used as intracellular messenger
This is due to calcium binds to the proteinn receptor Calmodulin , this causes the activation of CaM Kinase
CaM Kinase regulate the activity of many proteins including trancriptional proteins
What are enzyme linked Receptors
They are transmembrane proteins with ligand binding domains on extracellular ends
The cytoplasmic domain act as enzyme or form enzyme acting complex