Researchers of the Radboud University Nijmegen Medical Centre have demonstrated that hormones can also activate their receptors inside the cell. Until now, cell surface expression of hormone receptors was considered a necessity for their ability to transduce hormonal signals from the outside of the cell to the inside.
This discovery may allow a significant improvement for the treatment of patients suffering from one of the many disorders that are caused by failure of a particular hormone receptor to reach the cell surface. One of these disorders is nephrogenic diabetes insipidus.
The most common cause of the inheritable form of nephrogenic diabetes insipidus (NDI) are errors in the gene that encodes the vasopressin receptor, leading to absence of this receptor at the cell surface and making it unable to bind its hormone vasopressin. Vasopressin transmits signals from the brain to the kidney to induce water uptake from the pro-urine. Without cell surface receptors, the kidney cells are not able to hear these signals, leading to high urine production. As a result, patients need to drink large quantities of water in order to prevent dehydration. This disorder is relatively rare as NDI affects approximately 40 families in the Netherlands.
Kidney cells of NDI patients do produce vasopressin receptors, but as these have a disturbed structure, they remain trapped inside the cell and fail to reach the cell surface. Vasopressin is secreted by the pituitary and is transported to the kidneys via the blood. However, it cannot enter the cells to reach the receptor as it is unable to pass the cell membrane.
A researcher from Nijmegen, Dr. Joris Robben, under supervision of cell physiologist Dr. Peter Deen and clinical geneticist Prof. Dr. Nine Knoers, used synthetic molecules (CPAs) that act in a similar manner as vasopressin. In contrast to vasopressin, these compounds can cross the plasma membrane. Upon entry into the cell, these compounds were able to activate the vasopressin receptors that are trapped there. Apparently, the disturbed receptor structure does not prevent these trapped receptor from responding to hormones.
As a result of this activation, these cells produced so called water channels. These are small proteins that are present in the cell membrane, allowing water entry from the pro-urine into the cell. Now this has been shown in isolated cells, it will be investigated whether this also allows functional rescue in living organisms, such as animal models.
This discovery offers a hopeful perspective for patients suffering from NDI or similar disorders caused by hormone receptors that are trapped inside the cell. Examples of these are visual impairment by retinitis pigmentosa, certain forms of obesity and hyperthyroidism. Now it is known that mutant receptors can be activated inside the cell, hormone-like drugs can be developed that are able to pass the cell membrane to activate their respective receptors inside the cell.
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