I believe it’s always best to start with the basics in order to get a good foundation of knowledge on which to build upon. For this reason, I have gone back to the beginning with regards to chemokines and looked at them as a whole group. The following is what I consider to be the keys points that are relevant to my research.
What are Chemokines?
Chemokines are a type of intracellular signalling molecule that come under the umbrella term of cytokines. They are chemoattractant in nature which means they attract and recruit certain cells and bacteria towards distinct areas in order to carry out a specific function: this is what distinguishes them from other cytokines. They are produced in response to several stimuli including:
· Bacterial products
· Viruses
· Agents that cause physical damage to cells E.g. silica, alum, urate crystals in gout
Due to this fact, it is evident that they are heavily involved in immunity and responding to pathogens. This includes both the innate and adaptive immune systems as they act to induce chemotaxis in the early phases of infection as well as the in the later stages that require leukocyte recruitment (5).
How do they function?
Chemokines act on G-protein coupled receptors (GPCRs) to transmit their signal. These GPCRs have 7 transmembrane helices and are linked to trimeric G-proteins that have an attached GDP protein in the inactive state. The signalling process is by way of the classical GPCR pathway in which activation of the receptor and G-protein causes a dissociation of the three subunits into the α-subunit and the βγ-subunit. These subunits can then go on to activate other intracellular molecules independently and trigger various intracellular pathways including the phospholipase C pathway which can result in an increased intracellular calcium concentration.
How are chemokine receptors classified?
There are 4 types of chemokine and correspondingly 4 types of chemokine receptor that are classified based on their amino acid sequence near the terminus of the molecule. These are:
1. CC chemokine receptors
These have two adjacent cysteine residues in this region. They are termed CCR1-9 and the genes for these receptors are clustered mostly on chromosome 4. β-chemokines act here.
2. CXC chemokines receptors
The cysteine residues on these termini are separated by a single amino acid. CXCR1-6 is used to denote these receptors with α-chemokines acting on them. The genes that encode these receptors are clustered on chromosome 17.
3. CX3C chemokine receptor
Only one had been discovered: fractalkine or CX3CL1 which binds the sole receptor of this class CX3CR1. It has 3 amino acids between the two cysteine terminal residues.
4. XC chemokine receptors
The chemokines that bind these receptors are unique in that they only contain two cysteine residues. They attract T cell precursors to the thymus.
For this reason, the chemokines that act on these two distinct sets of receptors result in varying physiological effects. The CC chemokine receptors are what I will be elaborating on as I start to look more specifically at the CC chemokine receptor 2 (CCR2) and the diseases it is implicated in.
That’s enough background information! It’s not the most exciting and innovative bit of text but I believe it’s necessary in order to give context to my research. So I hope you haven’t become disheartened as I will endeavour to bring you the latest in chemokine therapeutics and those novel agents that will hopefully make a real difference to sufferers worldwide.
No comments:
Post a Comment