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Introduction

 

GPCR’s (G-Protein coupled receptors) accomplish the largest
and most diverse group of eukaryotic membrane proteins; playing a role at some
stage in almost every thinkable physiological process. Their widespread value
across the biological system can attributed to the versatility in their sensory
ability, with GPCR’s largely involved in processes such as vision, taste and
olfaction (smell), as well as their necessity in mediating cellular responses
to many hormones and neurotransmitters.

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At the most basic level these receptors share a
characteristic topology consisting of 
seven-transmembrane a-helices, interconnected by a series of extracellular and
intracellular loops. Despite
their conserved TM7 topology, a comparative genomic analysis of  N-terminal (extracellular) regions show little
sequence homolog (5)y; this, illustrating the particularly diverse catalogue of
ligands, including monoamines, chemokines, neurotransmitters, peptides and some
naturally occurring chemicals such as calcium ions (1)

Despite their
low sequence homology GPCR’s have been classified in accordance with both their
physiological and structural features, to a “GRAFS” system encompassing five categories;
Glutamate (G), Rhodopsin (R), Adhesion (A), Frizzled/Taste2 (F), and Secretin
(S) (2).

 

GPCR’s,
despite their sequence diversity, are known to function under the same
mechanism. The process involves the transduction of extracellular signals, in
the form of a bound ligand, into an intracellular response, mediated by the
intracellular activation of an associated heterotrimeric (abg) G-protein.
These G-proteins exist in an inactive a-GDP bound state but will exchange GDP
for GTP following ligand-induced conformational change in the TM7 region. This
exchange acts to activate the G protein, allowing it to separate from the
receptor into its Ga-GTP and Gbg(3), both active second messengers in
their own right, causing alterations in cell phenotype and gene expression.
Specificity of signal transduction is largely regulated by the controlled
expression of multiple Ga and Gbg variants(4),
each binding to different specific downstream targets, often activating or
inhibiting potent downstream messengers such as PKA (through increased cAMP
by binding adenylate cyclase), PLCb and PI3K. The signalling pathways for
activated heterotrimeric G-proteins, both the Ga-GTP and Gbg, have been somewhat elucidated to
also include various MAP3K-MAP2K-MAPK networks heavily involved in cell
viability including Raf-MEK1/2-ERK1/2, MAP3K-MKK3/6-p38MAPK and
MEKK2/3-MEK5-ERK5 among a few less defined others(5). The signalling system is
further fine-tuned through regulatory proteins such as RGS (Regulators of
G-protein signaling), which accelerate GTP hydrolysis on Ga-GTP subunits,
and GEFs (guanine exchange factors), which accelerate GDP exchange for GTP. The
system is further controlled through phosphorylation of GPCRs by GRKs (G
protein coupled receptor kinases), the binding of b-arrestin
scaffolds and clathryn-mediated  receptor
endocytosis (6) resulting in an intricately sensitive system.

 

GPCR’s are expressed
in almost all cell types and play important roles in a wide array of
physiological processes. 

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