Recent studies have AbMole 11-hydroxy-sugiol indicated it has been shown that differential activation of Gbc dimers alters many downstream signalling pathways that include the mitogen activate protein kinase cascade through RAS pathway in regulating the phosphoproteome. Extra cellular regulated Kinase 1 and 2 enzymes of the MAPK cascade are evolutionary conserved in regulating cell signal transduction by connecting cell-surface receptors to critical regulatory targets within cells. These pathways are essential in controlling cell survival, proliferation and apoptosis. The chicken genome only possess the mammalian orthologue of ERK2 suggesting that this gene later duplicated itself and evolved into ERK1 in a mammalian progenitor species, after the divergence of avian species. ERK1/2 activation has distinct role in modulating endocytosis either by sequestering or nonsequestering of the activated GPCR’s. Agonist occupied or constitutively activated GPCR’s are phosphorylated and desensitized by kinase molecules GRK’s, which are evolutionarily conserved and present in both mammals and chickens. GRK2 belongs to second sub family of GRK’s, which are specifically regulated by Gbc signalling upon their binding. These events have previously been shown to phosphorylate and desensitize its associated GPCR by regulating AbMole Isoforskolin arrestin binding and activating endocytosis pathways. The diversity in tissue expression of various Gb and Gc subunits suggests a role for Gbc signalling in regulating the traffic of GPCRs on cell membrane. Inherited variations in genes that alter the structure of Gb subunits are therefore likely to differentially activate the Gbc signalling potential to alter both phosphorylation and endocytosis potential of GPCR’s, in a timely dependent manner. Alternative splicing of the five genes that encode Gb subunits introduces even greater potential for the functional diversity of Gbc dimers. Interestingly a common human variant GNB3s subunit, coded by the 825T allele causes enhanced signalling in downstream targets of GNB3 and the hyper activation of functional G protein signalling pathways. The GNB3 825T allele has a frequency of between 21 to 91% in the different populations that have been studied to date. This allele has been shown to be a significant predisposing factor for common diseases such as Alzheimer’s, hypertension, obesity, low birth weight, increased ventricular mass and coronary heart disease. However, Bullido et al. demonstrated a significant increase in both MAPK activity and cAMP levels in HEK-293 cells transfected with recombinant GNB3 825T plasmid constructs, compared to 825C constructs. These results were consistent with observed biochemical changes in the brains of patients with Alzheimer’s disease. Despite the interest provoked by studies showing that the enhanced signalling of GNB3s causes an increase in the risk of developing brain disorders, hypertension and coronary heart disease in humans, a definitive understanding of the mechanisms underlying these pathologies has not yet been reached.