G-protein-coupled receptors (GPCR) consists of the largest family of drug targets. Many signaling systems depend on GPCR to convert external and internal stimuli to intracellular responses. They consist of a single polypeptide that is folded into a globular shape and embedded in a cell’s plasma membrane. They are also called seven-transmembrane receptors because of the presence of seven segments that run across the entire length of the cell membrane. GPCRs interact with G proteins in the plasma membrane. When an external signaling molecule binds to a GPCR, it causes a conformational change in the GPCR. This change then triggers the interaction between the GPCR and a nearby G protein. Whenever a G protein is active, both its GTP-bound alpha subunit and its beta-gamma dimer can relay messages in the cell by interacting with other membrane proteins involved in signal transduction. Specific targets for activated G proteins include various enzymes that produce second messengers, as well as certain ion channels that allow ions to act as second messengers. Some G proteins stimulate the activity of these targets, whereas others are inhibitory. As is the case with other membrane proteins, GPCRs are subjected to a stringent quality control mechanism at the endoplasmic reticulum, which ensures that only correctly folded proteins enter the secretory pathway. Because of this quality control system, point mutations resulting in protein sequence variations may result in the production of misfolded and disease-causing proteins that are unable to reach their functional destinations in the cell.
One mechanism through which the mutation could cause a lack of proper targeting is protein overexpression. Overexpression can simply reduce the steady-state levels of other proteins, by affecting their transcription, translation, or their rate of degradation. They can also activate new pathways through neomorphic effects. For instance, overexpression of cytoplasmic protein could lead novel phenotype due to the accumulation of sub-population in the nucleus.