Introduction GPCR’s (G-Protein coupled receptors) accomplish the largestand most diverse group of eukaryotic membrane proteins; playing a role at somestage in almost every thinkable physiological process. Their widespread valueacross the biological system can attributed to the versatility in their sensoryability, with GPCR’s largely involved in processes such as vision, taste andolfaction (smell), as well as their necessity in mediating cellular responsesto many hormones and neurotransmitters.At the most basic level these receptors share acharacteristic topology consisting of seven-transmembrane a-helices, interconnected by a series of extracellular andintracellular loops. Despitetheir conserved TM7 topology, a comparative genomic analysis of N-terminal (extracellular) regions show littlesequence homolog (5)y; this, illustrating the particularly diverse catalogue ofligands, including monoamines, chemokines, neurotransmitters, peptides and somenaturally occurring chemicals such as calcium ions (1)Despite theirlow sequence homology GPCR’s have been classified in accordance with both theirphysiological 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 samemechanism.
The process involves the transduction of extracellular signals, inthe form of a bound ligand, into an intracellular response, mediated by theintracellular activation of an associated heterotrimeric (abg) G-protein.These G-proteins exist in an inactive a-GDP bound state but will exchange GDPfor GTP following ligand-induced conformational change in the TM7 region. Thisexchange acts to activate the G protein, allowing it to separate from thereceptor into its Ga-GTP and Gbg(3), both active second messengers intheir own right, causing alterations in cell phenotype and gene expression.Specificity of signal transduction is largely regulated by the controlledexpression of multiple Ga and Gbg variants(4),each binding to different specific downstream targets, often activating orinhibiting potent downstream messengers such as PKA (through increased cAMPby binding adenylate cyclase), PLCb and PI3K. The signalling pathways foractivated heterotrimeric G-proteins, both the Ga-GTP and Gbg, have been somewhat elucidated toalso include various MAP3K-MAP2K-MAPK networks heavily involved in cellviability including Raf-MEK1/2-ERK1/2, MAP3K-MKK3/6-p38MAPK andMEKK2/3-MEK5-ERK5 among a few less defined others(5). The signalling system isfurther fine-tuned through regulatory proteins such as RGS (Regulators ofG-protein signaling), which accelerate GTP hydrolysis on Ga-GTP subunits,and GEFs (guanine exchange factors), which accelerate GDP exchange for GTP.
Thesystem is further controlled through phosphorylation of GPCRs by GRKs (Gprotein coupled receptor kinases), the binding of b-arrestinscaffolds and clathryn-mediated receptorendocytosis (6) resulting in an intricately sensitive system. GPCR’s are expressedin almost all cell types and play important roles in a wide array ofphysiological processes.