G proteins functions as key transducers of information across cell membranes by coupling receptors to effectors such as adenylyl cyclase (AC) or phospholipase C.They are part of a large family of proteins that bind and hydrolyze guanosine triphosphate (GPT) as part of an “on” and “off” switching mechanism. G proteins are heterotrimers, consisting of G?, G?, and G? subunits, each of which is encoded by a different gene.
Some strains of bacteria have developed toxins that can modify the activity of the ? subunit of G proteins, resulting in disease. For example, cholera toxin produced by the microorganism that causes cholera, vibrio cholerae causes ADP ribosylation of the stimulatory (G?s) subunit of G proteins. This modification abolishes the GTPase activity of G?s and results in an ?s subunit that is always in the “on” or active state. Thus, cholera toxin results in continuous stimulation of AC. The main cells affected by this bacterial toxin are the epithelial cells of the intestinal tract, and the excessive production of cAMP causes them to secrete chloride ions and water. This causes severe diarrhea and dehydration and may result death.
Another toxin, Pertussis toxin, is produced by Bordatella Pertussis bacteria and causes whooping cough. The Pertussis toxin alters the activity of G?i by ADP ribosylation. This modification inhibits the function of the ?i subunit by preventing association with activated receptors. Thus, the ?i subunit remains GDP-bound and in an “off” state, unable to inhibit the activity of AC. The molecular mechanism by which Pertussis toxin cause whooping cough is not understood.
The understanding of the actions of cholera and pertusis toxins highlights the important of normal G-protein function and illustrate that dysfunction of this signaling pathway can cause acute disease. In the years since the discovery of these proteins, there has been an explosion of information of G proteins and several chronic human diseases have been linked to genetic mutations that cause abnormal function or expression of G proteins. These mutations can occur either in the G proteins themselves or in the receptors to which they are coupled.
Mutations in G protein-coupled receptors (GPCRs) can result in the receptor being in an active conformation in the absence of ligand binding. This would result in sustained stimulation of G proteins. Mutations of G- protein subunits can result in either constitutive activation (e.g., continuous stimulation of effectors such as AC) or loss of activity (e.g., loss of cAMP production).
Many factors influence the observed manifestations resulting from defective G-protein signaling. These include the specific GPCRs and the G proteins that associate with them, their complex patterns of expression in different tissues, and whether the mutation is germ-line or somatic. Mutation of a ubiquitously expression GPCR or G protein results in widespread manifestations, while mutation of a GPCR or G protein with restricted expression will result in more focused manifestations.
Somatic mutation of G?s during embryogenesis can result in the deregulated activation of this G protein and is the source of several diseases that have multiple pleiotropic or local manifestations, depending on when the mutation occurs. For example, early somatic mutation of G?s and its overactivity can lead to McCune-Albright syndrome (MAS). The consequences of the mutant G?s in MAS are manifested many ways, with the most common being a triad of features that includes polyostotic (affecting many bones) fibrous dysplasia, café-au-lait skin hyperpigmentation, and precocious puberty. A later mutation of G?s can result in a more restricted focal syndrome, such as monostotic (affecting a single bone) fibrous dysplasia.
The complexity of the involvement of GPRS of G proteins in the pathogenesis of many human diseases is beginning to be appreciated, but already this information underscores the critical important of understating the molecule events involved hormone signaling to that rational therapeutic interventions can be designed.
- Harrison’s Principles of Internal Medicine, 17th edition.
- Davidson’s Principles and Practice of Medicine, 20th Edition
- Medical physiology, Lippincott Williams & Wilkins 3rd edition.