| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Pharmacology Carver College of Medicine The University of Iowa Iowa City, Iowa 52242
Address all correspondence and requests for reprints to: Dr. Mario Ascoli, Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242. E-mail: mario-ascoli{at}uiowa.edu.
The cloning of the cDNAs for the rat (1) and porcine (2) LH receptor (LHR) in 1989 provided us with new experimental tools that resulted in a tremendous explosion in our knowledge of the structure and functions of the LHR as well as the closely related FSH and TSH receptors (reviewed in Refs. 3, 4, 5, 6, 7). Some of the most important recent advances in this area include 1) the discovery that naturally occurring mutations of these three receptors are responsible for some endocrine disorders (7, 8, 9); 2) the generation of FSH receptor- (10) and LHR-null mice (11, 12); and 3) the recent report of the crystal structure of a portion of the extracellular domain of the FSH receptor bound to FSH (13).
One aspect of the biology of the LHR that has remained rather mysterious is the possibility that this receptor may be widely expressed in extragonadal tissues, thus making LH and chorionic gonadotropin (CG) pleiotropic rather than gonadal-specific hormones. Although there are many reports documenting the presence of LHR transcripts and/or protein in an ever-increasing number of extragonadal tissues (reviewed in Refs. 14, 15, 16, 17), the significance of these findings remains, for the most part, poorly understood. In this issue, Apaja et al. (18) add new fuel to the fire by documenting that the maturation of the intracellular precursor of the rat (r) LHR into the mature cell-surface protein (i.e. the LHR that is exposed to circulating gonadotropins) is a regulated process. They show that the developing rodent gonads, as well as several extragonadal tissues, express only the immature form of the LHR, whereas other tissues such as the mature gonads, adult female adrenal, and the kidneys of pregnant rats express both the immature and the mature LHR. The studies of Apaja et al. (18) are particularly convincing because they studied the expression of the LHR using several experimental approaches such as expression of a LacZ reporter driven by the murine LHR promoter and nested PCR to assess the presence of LHR transcripts. Finally, affinity purification or immunoprecipitation was also used to assess the expression of different forms of the LHR protein.
Rodent and porcine ovaries and testes express at least two forms of the LHR, an 85- to 95- and a 68- to 75-kDa protein 1 (20, 21, 22, 23, 24, 25). Studies on the nature of these two forms of the LHR have been conducted mostly in mammalian cells transfected with the cDNAs for the porcine, rat, or human (h) LHR (reviewed in Ref. 4). The 85- to 95-kDa band present in transfected cells is the mature LHR located at the cell surface, as judged by surface biotinylation of intact cells and its susceptibility to degradation by surface proteolysis, neuraminidase and PGNase F (22, 26, 27). In contrast, the 85- to 95-kDa LHR is not susceptible to EndoH, a glycosidase that removes the type of carbohydrate side chains associated with immature glycoproteins that reside in the endoplasmic reticulum (21, 22, 28, 29). Conversely, the 68- to 75-kDa appears to be located intracellularly because it is readily susceptible to EndoH digestion and it cannot be detected by surface biotinylation of intact cells (21, 22, 26, 28). This form of the LHR is also insensitive to surface proteolysis and neuraminidase digestion (22, 26, 27, 28, 29). Biosynthetic labeling of heterologous cells transfected with rLHR also revealed that the 68- to 75-kDa rLHR is a precursor of the 85- to 95-kDa rLHR (22, 29). In transfected cells, the conversion of the immature to the mature form of the rLHR is a slow and inefficient process, however, and a large proportion of the immature rLHR is never converted to the mature receptor (22, 30, 31, 32, 33). Importantly, the immature form of the rLHR can bind hCG with the same affinity as the mature rLHR (27), but the binding affinity of ovine LH for the mature rLHR is higher than its binding affinity for the rLHR precursor (34). Clearly then, although the immature rLHR has attained a conformation that permits hormone binding, this conformation is not the same as that of the mature form of the rLHR. In addition, because of its intracellular location, the immature LHR cannot come in contact with circulating gonadotropins.
In documenting the presence of the immature, but not the mature, form of the LHR in the developing rat gonads, the studies of Apaja et al. (18) are interesting because they imply that these tissues are not sensitive to gonadotropin stimulation. Their finding is in perfect agreement with the phenotype of the LHR-null mice that display no abnormalities in sexual differentiation (11, 12). In fact, an important conclusion established from the phenotype of these animals is that sexual differentiation in rodents is independent of gonadotropin actions (11, 12). This, of course, is in contrast with the need for gonadotropin action during sexual differentiation in humans. 46XY individuals who are homozygous (or compound heterozygous) for loss-of-function mutations of the LHR display various degrees of feminization of their external genitalia (8, 9). Herein lies an important difference between sexual differentiation in rodents and humans that may be related to the processing (or the regulation of the processing) of the immature to mature forms of the LHR in these two species. It is already known that at steady state the relative abundance of the mature LHR is much lower than that of the immature LHR in cells transfected with the rLHR, but the mature form of the LHR is more abundant than the immature form in cells transfected with the hLHR (reviewed in Ref. 4). If this is also true in human and rat gonadal cells then the developing human gonads are likely to be more sensitive to gonadotropins because they would express more LHR at the cell surface than do the rat gonads. From an evolutionary standpoint this would fit nicely with the presence of a gonadotropin of pregnancy (hCG) in humans but not in rodents.
The increased level of mature rLHR in the adrenals and kidneys of pregnant rats reported by Apaja et al. (18) is also interesting because it shows that the maturation of the LHR is under physiological control. Because it has already been shown that the expression of the LHR mRNA is regulated at transcriptional and posttranscriptional steps (reviewed in Ref. 35), these findings add a new layer of complexity to the different processes that are involved in the regulation of the expression of the cell-surface LHR. Moreover, because the temporal expression of the mature LHR in the pregnant adrenal and kidneys coincides with the differentiation of the fetal urogenital structures, it suggests that the ability of these two tissues to respond to gonadotropins may be involved in sexual differentiation in rodents.
Lastly, because most extragonadal tissues express only the immature LHR (18) and this form of the LHR is not exposed to the hormone, it appears that most of the extragonadal LHR expression may have little or no physiological significance. There are some tissues in which this is clearly not the case, however. Adult and developing rat nervous tissue (23) and the pregnant rat kidney and adrenal gland appear to be notable exceptions (18). The adrenal expression of the mature LHR is or particular interest because several other groups have previously reported the presence of functional LHR in the adrenals of transgenic or knockout mouse models with elevated levels of gonadotropins (36, 37, 38, 39) and in the adrenals of some women who experience Cushing’s syndrome (40, 41).
In summary, the paper by Apaja et al. (18) documents novel aspects of the developmental and physiological regulation of the processing of the LHR, and it raises the bar for future studies on the extragonadal expression of the LHR. Such studies will now have to carefully consider whether the expressed LHR protein is the mature or immature form of the receptor. In addition, these studies raise a number of questions regarding the physiological, cellular, and molecular aspects of the regulation of the processing and maturation of the LHR.
 |
Footnotes |
|---|
1 A third form of the LHR with an apparent mass of 165 kDa that is also observed in transfected cells appears to be an oligomer of the 68- to 75-kDa LHR (4 19 ). 
Received May 16, 2005.
Accepted for publication May 18, 2005.
|
References |
|---|
 Top References |
|---|
-subunit promoter/simian virus 40 T-antigen fusion gene. Mol Cell Endocrinol 12:801–809This article has been cited by other articles:
 |
|
 |
|
  W. Luo, Y. Wang, T. Hanck, R. Stricker, and G. Reiser Jab1, a Novel Protease-activated Receptor-2 (PAR-2)-interacting Protein, Is Involved in PAR-2-induced Activation of Activator Protein-1 J. Biol. Chem., March 24, 2006; 281(12): 7927 - 7936. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
