GS-Activating Receptors: Modes of Transmembrane Signalling and Genetic Defects
| Title: | GS-Activating Receptors: Modes of Transmembrane Signalling and Genetic Defects |
|---|---|
| Authors: | Hendy, PhD, Geoffrey N.; Gudermann, Thomas; Bichet, Daniel G.; Arthus, Marie-Francoise; Seibold, Anita; Rosenthal, Walter; Birnbaumer, Mariel; Lonergan, Michele; Birnbaumer, Lutz; Antaramian, Anaid |
| Publisher: | Advances in Second Messenger and Phosphoprotein Research |
| Date Published: | January 01, 1993 |
| Reference Number: | 244 |
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
A G-protein-coupled receptor (GPCR) is a receptor which is anchored in the cell membrane and coupled to a G-protein located immediately beneath the cell membrane. When the GPCR binds with its extracellular agent, it causes changes in the G-protein to which it is coupled. These changes allow the message carried by the extracellular agent to be passed along to the next molecular structures, called the second messengers, which will continue to pass along the extracellular agent's signal. For example, when the antidiuretic hormone, arginine vasopressin (AVP) binds with its receptor, a GPCR called vasopressin-2 (V2R), it causes the Gs-protein to which it is coupled to temporarily split into two subunits. This allows the Gs protein to stimulate the enzyme, adenylyl cyclase (AdC). Stimulated AdC elevates the level of the metabolic regulator, cAMP. The AdC/cAMP complex is the second messenger which sends the signal of AVP along the proper sequence, the physiological result of which is to allow the kidneys to concentrate urine and reabsorb body-water flowing through the kidney collecting ducts.
V2R interacts with one extracellular agent, AVP, and one G-protein, the Gs-protein, to activate a single second messenger, the AdC/cAMP system. The authors' data indicates that other receptors can activate two second messenger systems. For example, the luteinizing hormone receptor (LHR), also coupled to a Gs-protein, can activate both the AcD/cAMP system and the PLC/IP3/CA2+ system. The mechanism by which Gs-activating receptors activate these two effectors is not yet known. However, two separate models for how this may occur are offered. In the first model, the receptor, once activated by its extracellular agent, interacts with two G-proteins, Gs and Gp. In the second, the activated receptor interacts with only the Gs protein. The Gs protein is made up of three subunits: alpha, beta and gamma. According to this model, when activated by the receptor, the alpha subunit activates the AdC/cAMP pathway and the beta and gamma subunits activate the PLC/IP3/CA2+ pathway.
The authors also provide conclusive data that X-linked congenital nephrogenic diabetes insipidus (CNDI) is caused by a mutation in the V2R gene. First, they note that the NDI causing gene and the V2R gene have the identical location in the X-chromosome, namely the q28 region. Second, the researchers were able to clone V2R , determine its normal structure, and compare it to the structure of V2Rs from NDI patients from two unrelated families.
The authors were able to determine that the V2Rs of the NDI patients of each family were mutated. The mutations differed between each family. But though the two mutations were different, and each altered the structure of the V2Rs for which they encoded differently, both mutations rendered the V2Rs dysfunctional. Normal V2Rs were found in the healthy males in both families, and the mothers were found to carry a mutated V2R gene on one of their X-chromosomes and a normal V2R gene on their other X-chromosome. This pattern is consistent with the X-linked recessive inheritance pattern of NDI.
Researchers strongly suspect that V2Rs are located outside as well as inside the kidney. Outside the kidney, they mediate different physiologic responses than inside the kidney. The NDI patients of both families showed no responses in their V2Rs either inside or outside the kidneys. This indicates a general V2R malfunction, which strengthens the case for mutated V2R genes being responsible for X-linked CNDI.