G CXCL8 is an inflammatory mediator chemokine which

G protein coupled receptors (GPCR)
are large protein family of receptors whose primary function is to transduce
extracellular stimuli such as neurotransmitters, chemokine, hormones, lipids,
and many other into intracellular signals. Transduction of signals results in
physiological processes such as sensations of sight, smell, taste, chemotaxis,
blood pressure and regulation of metabolism. Chemokines are small peptides
which induces intracellular signals upon binding with a cell-surface receptors.
They are powerful activators and chemoattractant for leukocytes which play a
crucial role in chemotaxis and angiogenesis. Chemokine receptors are members of
the GPCR. Chemokine receptors are divided into 4 subclasses name as CXC, CX3C,
CC and C according to the cysteine position in the amino acid sequence. These
receptors are expressed on the membranes of leukocytes to induce chemotaxis.
Chemokine receptors are known to be involved in several disease conditions
especially in inflammations and infectious disease such as allergy, psoriasis,
malaria and human immunodeficiency virus (HIV).

G protein coupled chemokine
receptors comprises of a 7 transmembrane spanning protein present in the plasma
membrane of the cell (Figure 1). The N-terminus present in the exterior is
crucial for the chemokine ligand binding while the C- terminus in the cytoplasm
is crucial for the heterotrimeric G protein coupling. G protein are made up of
3 subunits, alpha (?), beta (?) and gamma (?) subunits in
which they are attached to the cytoplasmic face of the plasma membrane by
lipids. Without a ligand binding, the G protein are inactive and it comprises of
GDP bounded with G? and G?? dimer (figure 2).

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Interleukin-8 (IL-8) which is also
known as a monomer or dimer CXCL8 is an inflammatory mediator chemokine which
is responsible in recruiting neutrophils and other granulocytes during
inflammation and is also an angiogenic factor for angiogenesis. IL-8 can bind
to CXCR1 or CXCR2 which is a GPCR to initiate intracellular signalling cascade.
Upon binding to the GPCR, it
becomes activated and undergoes conformational change. GDP is replaced by GTP
on the G? subunit. Following this, G?? dimer
gets dissociate from G? subunit. The G? subunit
will regulate target protein such as adenylate cyclase and the G?? dimer may
act upon phospholipase C. Stimulation of these enzymes activates the MAPK
signalling. These modifies gene expression to promote cell survival,
proliferation and inflammation. Inositol triphosphate (IP3) causes the release
of intracellular calcium where it will results in degranulation. Signalling via
MAPK and phosphatidylinositol-3 kinase (PI3) produces adhesion molecules,
integrin and MAC-1 which is required for chemotaxis. Therefore, IL-8 enables
recruitment and stimulation of neutrophils via intricate signalling and
adhesion molecules. Within minutes, after the release
of IL-8 from GPCR, GTP is hydrolysed back to GDP and gets bounded to G?
subunit and
G?? dimer will be reassociate forming the inactive G protein.

G protein coupled chemokine
receptors plays a role in various pathologies such as cancer HIV and many more.
Cancer is a disease in which there in uncontrolled cell growth and
proliferation. Chemokine GPCRs that has a prominent roles in cancer are CXCR2
and CXCR4 in which there promote cancer angiogenesis. CXCR4 gpcr and its ligand
CXCL12 (SDF-1) is secreted by cancer cells to induce chemotaxis migration and
infiltration of endothelial cells into the tumour tissues. CXCL12 are
homeostatic chemokine which is found on many organs such as lung, liver, heart
and kidney.  CXCR4 is widely expressed on
B and T-lymphocytes, monocytes, macrophages and many more. When CXCL12 binds to
CXCR4 GPCR, GDP is released and being replaced by GTP result in dissociation of
G?? dimer
and G? subunit. Multiple series of signal
transduction is carried out as seen in figure 4. G?i inhibits adenylyl cyclase and thus less cAMP is
present in the cell. G? activates
phospholipase c and this activates the IP3 to cause a release of intracellular
calcium. DAG is also activated which leads to chemotaxis of cells. The most
prominent pathway of CXCR4-CXCL12 is the activation of PI3K pathway by G?? and G?. PI3K
activates AKT in which it has a significant role in tumour cell survival and
cell proliferation. On top of that, p38 and ERK1/2 are also included in promoting
tumour cell survival. Firstly, ERK is known for phosphorylation and activation
of cellular proteins. Secondly, it can move into the nucleus to stimulate
transcription factor and disrupt cell cycle progression. CXCL12 will cause an
increase in vascular cell adhesion molecules where they are key proteins in
tumour cell invasion. Hence, the attachment of chemokine CXCL12 to CXCR4
receptor result in numerous transduction pathway being activated and this leads
to tumour progression by angiogenesis, metastasis and survival.

HIV infection is one disease that
mediate the use of GPCRs. The viral entry into the cell is through the CXCR4 or
CCR5 receptor. CXCR4 receptor is an alpha-chemokine specific to SDF-1. CCR5 is
a chemokine receptors in the CC chemokine group and is present on various cells
such as T cells, macrophages and dendritic cells. HIV env protein firstly binds
to CD4 and result in a conformational change of HIV gp120 glycoprotein and
exposing the V3 loop. Gp41 glycoprotein proceeds to bind with the CXCR4 or CCR5
receptor resulting in fusion of HIV and the cell membrane (Figure 5). Thus,
chemokine receptor not only produces proinflammatory signals, but also serve as
an entrance for HIV virus to enter and infect the cell. There are
anti-retroviral drugs available called HIV fusion inhibitors which are CCR5
antagonist such as Maraviroc and Vicriroc. These drugs will prevent the fusion
of HIV with the cell membrane.  

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