Desensitization of the Human V2 Vasopressin Receptor. Homologous Effects in the Absence of Heterologous Desensitization

Title: Desensitization of the Human V2 Vasopressin Receptor. Homologous Effects in the Absence of Heterologous Desensitization
Authors: Birnbaumer, Mariel; Antaramian, Anaid; Themmen, Axel P.N.; Gilbert, Stephanie
Publisher: Journal of Biological Chemistry
Date Published: June 15, 1992
Reference Number: 426
Three main pathways have been implicated in desensitization of receptors that stimulate adenylylcyclase (AC): cAMP-mediated phosphorylation; cAMP-independent phosphorylation, and receptor internalization. Cell lines derived from the murine Ltk-cell were found useful in exploring the contribution of cAMP-dependent phosphorylation in V2 vasopressin receptor desensitization. The HTB-2 cell expresses the human V2 vasopressin receptor, introduced by transfection of human genomic DNA, and the prostaglandin E1 (PGE1) receptor, endogenous to the Ltk- cell. The A7 cell expresses the hamster beta 2-adrenoceptor, which undergoes the above-mentioned desensitization processes. Treatment of HTB-2 cells with arginine vasopressin (AVP) had no effect on AC responsiveness to PGE1, but promoted desensitization of the AVP response. This was seen as a 5-6-fold right shift in the dose-response curves for AVP action (cAMP accumulation in intact cells and AC stimulation in homogenates and isolated membranes) and in a decrease in the maximum effect of AVP on these parameters. AVP treatment caused a decrease in cell surface receptors to approximately 75% of control without changes in KD, as determined by Scatchard analysis. When cAMP was increased by treatment with 10 microM PGE1 and isobutylmethylxanthine, desensitization of the PGE1 receptor was observed but not of the AVP receptor. In A7 cells the same treatment caused, as expected, a 3-fold right shift in the dose-response curve for AC stimulation by isoproterenol, indicating that L cells can mediate heterologous desensitization. These data demonstrate that the V2 vasopressin and the PGE1 receptors undergo homologous desensitization in the absence of cAMP-mediated phosphorylation and that this component is not required for vasopressin receptor internalization.
The publisher has not granted permission to reproduce this article on our website.
You may, however, read this article at the Journal of Biological Chemistry website. In order to view this document, you will need Acrobat Reader. If you do not already have Acrobat Reader or need to upgrade, click here.
To return to this page, use your "back" key.

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)

When cells are subject to continued exposure to hormonal stimulation, they gradually lose their response to it. This naturally occurring phenomena is called desensitization. Desensitization is a necessary part of the receptor cycle; it prevents the cell from being overstimulated, and prevents the hormonal process initiated when the hormone binds with its receptor from carrying on too long.

Receptors are molecular structures within cells or on the cell surface that bind with extracellular messengers such as hormones or neurotransmitters. There are receptors that stimulate the enzyme, adenylyl cyclase (AC). For example, the vasopressin-2 receptor (V2R), when bound with the antidiuretic hormone, arginine vasopressin (AVP), stimulates AC. AC, in turn, elevates cellular levels of cAMP. This molecular sequence is part of the sequence that allows the kidney to reabsorb water and concentrate urine.

V2Rs undergo desensitization, and Birnbaumer, et al., sought to clarify its desensitization process. The authors developed a cell line that expressed V2Rs. When this cell line was infused with AVP, it resulted in desensitization to AVP as indicated by a lessening of stimulation of AD. (As stated, when AVP first binds with V2R, it results in the stimulation of AD, which leads to kidney water reabsorption. But after it has done its job, the V2R must desensitize itself to AVP to temporarily turn off the water reabsorption process.)

The cells were cultured and treated with test substances such as AVP, prostaglandin E1 (PGE1) and a general prostaglandin inhibitor called IBMX. Then the cell cultures were tested for their levels of AVP/V2R binding, cAMP accumulations and AC stimulation. The authors wanted to know whether the V2R desensitization is induced by AVP itself, another agonist, or by activation of other receptors in the cell.

Desensitization may either be homologous or heterologous. It is homologous when it is caused by an agonist occupying a receptor, e.g. AVP occupying V2R. It is heterologous when the desensitization is caused by activation of other receptors that increase intracellular cAMP. For example, V2R desensitization would be heterologous if it was caused by some other receptor(s) in the cell culture increasing the cAMP levels.

The authors' experiments indicated that V2R desensitization is homologous. They concluded that AVP induces the V2R desensitization process, which is characterized by:
  1. a loss in the number of high affinity binding sites on the cell surface (probably due to a process called internalization).
  2. a loss of potency and efficacy to induce cAMP accumulation in the cells, and
  3. a loss of potency and efficacy in stimulating AC after the cells' integrity have been disrupted.