Defects of G Protein-Coupled Signal Transduction in Human Disease
| Title: | Defects of G Protein-Coupled Signal Transduction in Human Disease |
|---|---|
| Author: | Spiegel, M.D., Allen M. |
| Publisher: | Annual Review of Physiology |
| Date Published: | 1996 |
| Reference Number: | 43 |
G proteins couple receptors for many hormones and neurotransmitters to effectors that regulate second messenger metabolism. G protein-coupled receptors comprise a superfamily with the common structural feature of a single polypeptide with seven membrane-spanning domains. G proteins themselves are heterotrimers with an alpha subunit that binds quanine nucleotides. In the basal state, G proteins tightly bind GDP; receptor activation allows exchange of bound GDP for GTP that activates the G protein and causes it to modulate effector activity. An intrinsic GTPase activity hydrolyzes bound GTP to GDP thereby deactivating the G protein. The effects (cholera, whooping cough) of bacterial toxins that target G proteins for covalent modification signal the potential importance of G protein dysfunction as a cause of human disease. Conceptually, G protein dysfunction could involve gain or loss of function. For Gs, examples of both types have already been defined. Mutations in G protein-coupled receptors have also been identified in several human diseases. Germline loss of function mutations in rhodopsin, cone opsins, the V2 vasopressin receptor, ACTH receptor, and calcium-sensing receptor are responsible for retinitis pigmentosa, color blindness, nephrogenic diabetes insipidus, familial ACTH resistance, and familial hypocalciuric hypercalcemia, respectively. Missense mutations that cause constitutive receptor activation have been identified in the TSH and LH receptors.
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)
The receptor has to get its message to the effector for the hormonal message to be carried out. In many cases it can because both the receptor and the effector are connected to the same G protein, so the G protein will be the medium through which the receptor transmits its message to the effector. These G proteins convey information carried by extracellular messengers from the outside to the inside of the cell by coupling receptors to effectors. Receptors that are coupled to G proteins are called G protein-coupled receptors (GPCRs).
GPCRs sit within cell membranes, the thin layer of tissue that forms the cell walls separating the inside from the outside of the cell. Think of GPCRs as a long string. Most of the receptor sits within the membrane in seven clumps called transmembrane helices. Part of the receptor snakes outside the cell, forming three curves called extracellular loops 1, 2 and 3. Part of the receptor snakes inside the cell three, possibly four, times forming intracellular loops 1, 2, 3 and possibly 4. (Look at diagram of GPCR.)
When either the G protein or the GPCR isn't functioning properly, it can result in human disease. Many mutations in both the G protein and in GPCRs have been identified and associated with specific disorders. The mutations may either be acquired at some point in a person's life or inherited from his or her parents. Mutations that are acquired during a person's life (somatic mutations) are not transmitted to his or her progeny, whereas inherited mutations (germline mutations) may be.
Germline mutations of genes that are expressed throughout the physiology will often cause generalized manifestations. Germline mutations of genes with a restricted range of expression and mutations in somatic genes expressed throughout the body will generally cause more localized manifestations. Mutations of the G protein or GPCR can result in either a loss or gain of function, both of which will result in disorder.
Loss-of-function mutations in GPCR genes (the genes that code for and create GPCRs) can result in misshapen receptors and/or an inability for the receptor to travel through the cell to reach its intended work site. GPCR mutations can prevent the receptor from binding with the hormone or neurotransmitter as it should. These mutations can also prevent the receptor from properly coupling with the G protein. Mutations in G proteins can block the receptor from coupling with the G protein, or prevent the receptor from activating, or interfere with the effector's ability to receive or pass on its message. All these will cause a loss-of-function disorder.
It has been hypothesized that GPCRs change shape in response to hormonal stimuli to be able to couple with G proteins. Sometimes GPCR mutations may result in the receptor changing shape in order to couple with G proteins independently of hormonal stimuli, thereby activating the G protein out of proper sequence. Mutations of the G protein itself may inhibit it from effectively interacting with the effector it is coupled to.
In his article, Spiegel lists and explains many diseases caused by GPCR mutations. However, because readers at this site are most interested in nephrogenic diabetes insipidus (NDI), we are focusing on mutations of the V2 vasopressin receptor (V2R), the GPCR that receives the message of the antidiuretic hormone, vasopressin. Mutations of the V2R can result in NDI.
Vasopressin acts on V2Rs found in the kidney that are coupled to G proteins. This begins a process that enhances water absorption and increases urine concentration. Mutations in the V2R render it incapable of responding to vasopressin. This results in an incapacity to concentrate urine. Symptoms of NDI include chronic excessive thirst and urination. Because the V2R gene is located on the X chromosome and males inherit only one copy of the X chromosome, it is generally males that are affected clinically by NDI when they inherit a mutated V2R. Women who inherit a mutated V2R generally manifest no symptoms of NDI, since the normal V2R gene on their other X chromosome is adequate for normal vasopressin responsiveness. Symptoms in NDI may manifest as early as the first week of life, and if it is not recognized early, severe bouts of dehydration resulting from the inability to concentrate urine could cause physical and mental damage. However, if detected early, damage of this type can be avoided as NDI is a manageable, if not yet curable, disorder.
Mutations of the V2R cause, then, a loss-of-function disorder. Many different mutations in the V2R have been discovered, covering almost every region of the receptor: the extracellular and intracellular loops, the transmembrane helices, and the tail ends of the receptor. In addition to the mutations being in different places, there are different types of mutations: missense, nonsense and frameshift. Nonsense and frameshift mutations arrest the development of the V2R, and it stops short of its normal length and eliminates a portion of the genetic information it carries. A missense mutation changes a part of the gene so it produces a different amino acid in the receptor's sequence than it is supposed to.