G-Protein Diseases

Iiri, T., Farfel, Z., and Bourne, H. R. (1998). G-protein diseases furnish a model for the turn-on switch. Nature 394, 35-38. 

Farfel Z, Bourne HR, liri T. The expanding spectrum of G protein disease. N Engl J Med 1999 340 1012-20. 

Z. Farfel, H. R. Bourne, and T. liri The expanding spectrum of G protein diseases. New England Journal of Medicine 340, 1012 (1999). 

Barrett EJ. The thyroid gland. In Boron WF, Boulpaep EL, eds. Medical Physiology A Cellular and Molecular Approach. Philadelphia, PA W.B. Saunders, 2003. Farfel Z, Bourne HR, liri T. Mechanisms of disease the expanding spectrum of G protein diseases. N Engl J Med 1999 340 1012-20. 

An increasing number of diseases are known to be linked to defects in receptor stmcture, function, or coupling. The defects may He at several locations in the stmcture of the receptor, which may alter its abiHty either to bind dmgs, to be inserted into the membrane, or to couple to effectors (including G-proteins) in the coupling protein or in the presence of autoantibodies, which can proceed to activate, block, or lyse the receptors and its components (96—99). 

Stmctural defects at the receptor level are determinant for a number of receptor diseases. In nephrogenic diabetes insipidus, where patients void large volumes of dilute urine even in the presence of vasopressin (antidiuretic hormone) (105), the disease is linked to mutations in three discrete regions of the G-protein-linked vasopressin (V2) receptor (106,107). 

Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone (98,108). This disease takes various forms, including Albright s hereditary osteodystrophy, which has unusual physical features and a generalized resistance to G-protein-linked hormones that function through cAMP as a second messenger. This defect is associated with a deficiency in the levels of the a-subunit of (109). Because this defect may be generalized, such patients also have olfactory dysfunction (110). 

PARs are coupled to multiple G-proteins and mediate a number of well-defined cellular responses via classical second messenger and kinase pathways. PARs are differentially expressed in cells of the vasculature as well in the brain, lung, gastrointestinal tract, skin as well as other highly vascularised tissues and evidence suggests distinct physiological functions and roles in disease states [2]. 

While the fluid mosaic model of membrane stmcture has stood up well to detailed scrutiny, additional features of membrane structure and function are constantly emerging. Two structures of particular current interest, located in surface membranes, are tipid rafts and caveolae. The former are dynamic areas of the exo-plasmic leaflet of the lipid bilayer enriched in cholesterol and sphingolipids they are involved in signal transduction and possibly other processes. Caveolae may derive from lipid rafts. Many if not all of them contain the protein caveolin-1, which may be involved in their formation from rafts. Caveolae are observable by electron microscopy as flask-shaped indentations of the cell membrane. Proteins detected in caveolae include various components of the signal-transduction system (eg, the insutin receptor and some G proteins), the folate receptor, and endothetial nitric oxide synthase (eNOS). Caveolae and lipid rafts are active areas of research, and ideas concerning them and their possible roles in various diseases are rapidly evolving. 

The a subunits and the Py complex have actions independent of those on adenylyl cyclase (see Figure 43-4 and Table 43-3). Some forms of tt stimulate channels and inhibit Ca channels, and some ttj molecules have the opposite effects. Members of the G, family activate the phospholipase C group of enzymes. The py complexes have been associated with channel stimulation and phospholipase C activation. G proteins are involved in many important biologic processes in addition to hormone action. Notable examples include olfaction (oColf) <1 vision (aj. Some examples are listed in Table 43-3. GPCRs are implicated in a number of diseases and are major targets for pharmaceutical agents. 

Arvanitakis L et al Constitutively signaling G-protein-coupled receptors and human disease. Trends Endocrinol Metab 1998 9 27. 

Bondy, B., Baghai, T. C., Zill, P. etal. (2002). Combined action ofthe ACE D- and the G-protein beta3 T-allele in major depression a possible link to cardiovascular disease Mol. Psychiatry, 7, 1120-6. 

Mimics, K., Middleton, F. A., Stanwood, G. D., Lewis, D. A. and Levitt, P. (2001), Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia , Mol. Psychiat.,... 

An increasing number of G proteins and RGS proteins have been deleted or overexpressed in genetic mutant mice. Not surprisingly, some of these mice exhibit complex behavioral abnormalities and in some cases abnormal responses to psychotropic drugs. These data further highlight the importance of G protein signaling in the brain in health and disease and open new paths for investigation in the years ahead. 

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