Identification and Structural Characterization of the Neuronal Luteinizing Hormone Receptor Associated with Sensory Systems

Apaja, Pirjo M.; Harju, Kirsi; Aatsinki, Jyrki T.; Petäjä-Repo, Ulla E.; Rajaniemi, Hannu

doi:10.1074/jbc.m311395200

Cited by 80 publications

(69 citation statements)

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“…Whether such a regulatory role could be assigned to other splice variants of the LHR in general is not known. However, this is a very likely possibility, because changes in physiological stimuli (Lakkakorpi et al, 1993;Licht et al, 2003), cellular differentiation (Sokka et al, 1992;Tena-Sempere et al, 1994;Zhang et al, 1994;Apaja et al, 2004Apaja et al, , 2005 and tumorigenic cell growth (Lin et al, 1994;Reinholz et al, 2000;Jiang et al, 2002;Steinmeyer et al, 2003) have all been shown to regulate the splicing pattern of the receptor.…”

Section: Discussionmentioning

confidence: 99%

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Luteinizing Hormone Receptor Ectodomain Splice Variant Misroutes the Full-Length Receptor into a Subcompartment of the Endoplasmic Reticulum

Apaja

Tuusa

Pietilä

et al. 2006

MBoC

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The luteinizing hormone receptor (LHR) is a G protein-coupled receptor that is expressed in multiple RNA messenger forms. The common rat ectodomain splice variant is expressed concomitantly with the full-length LHR in tissues and is a truncated transcript corresponding to the partial ectodomain with a unique C-terminal end. Here we demonstrate that the variant alters the behavior of the full-length receptor by misrouting it away from the normal secretory pathway in human embryonic kidney 293 cells. The variant was expressed as two soluble forms of M r 52,000 and M r 54,000, but although the protein contains a cleavable signal sequence, no secretion to the medium was observed. Only a very small fraction of the protein was able to gain hormone-binding ability, suggesting that it is retained in the endoplasmic reticulum (ER) by its quality control due to misfolding. This was supported by the finding that the variant was found to interact with calnexin and calreticulin and accumulated together with these ER chaperones in a specialized juxtanuclear subcompartment of the ER. Only proteasomal blockade with lactacystin led to accumulation of the variant in the cytosol. Importantly, coexpression of the variant with the full-length LHR resulted in reduction in the number of receptors that were capable of hormone binding and were expressed at the cell surface and in targeting of immature receptors to the juxtanuclear ER subcompartment. Thus, the variant mediated misrouting of the newly synthesized full-length LHRs may provide a way to regulate the number of cell surface receptors. INTRODUCTIONNewly synthesized proteins destined for the secretory pathway enter the endoplasmic reticulum (ER) and after correct folding and assembly are either secreted from the cell or transported to their site of action in other cellular compartments. Folding of the nascent proteins is constantly monitored by the ER quality control apparatus. It has an important task in maintaining the cellular homeostasis by preventing premature export of incompletely folded and assembled proteins and removing misfolded and unassembled ones via the ER-associated degradation (ERAD) pathway, presumably by recognizing structural signals that are enriched in incompletely folded proteins (Ellgaard and Helenius, 2003;Helenius and Aebi, 2004). Recent evidence suggests that the ER quality control does not only target permanently misfolded proteins to ERAD but may also dispose some folding competent ones, possibly due to their slow folding kinetics. This applies also to several polytopic membrane proteins, including G protein-coupled receptors (GPCRs; Petäjä-Repo et al., 2000;Imai et al., 2001;Lu et al., 2003;Wü ller et al., 2004;Pietilä et al., 2005). Thus, export from the ER is the limiting step in their expression and probably provides a mean to regulate the number of functional receptors at the cell surface. This is supported by our recent finding that final maturation of the rat luteinizing hormone receptor (rLHR) was found to be developmentally regulated in targ...

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Section: Discussionmentioning

confidence: 99%

“…Antibody coupling was performed according to the instructions of the manufacturer using 50 l of antisera for 100 l of resin (Bio-Rad). Ligand affinity chromatography was performed using Affi-Gel 10 -coupled hCG, as described previously (Apaja et al, 2004). Glycerol 20% (vol/vol) was added to all buffers and 140 mM NaCl to buffer E instead of buffer B.…”

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Luteinizing Hormone Receptor Ectodomain Splice Variant Misroutes the Full-Length Receptor into a Subcompartment of the Endoplasmic Reticulum

Apaja

Tuusa

Pietilä

et al. 2006

MBoC

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“…The novel actions suggested include improvement of blastocysts implantation (Han et al, 1999), regulation of oviduct and cervix function (Lei et al, 1993a;Lin et al, 2003), improvement of endometrial angiogenesis and growth (Filicori et al, 2005), and a role in brain development and sexual behaviour (Lei et al, 1993b;Apaja et al, 2004). However, despite the numerous findings on existence of extragonadal LH/hCG-Rs their physiological significance has remained unclear, and in vivo evidence for their functionality and necessity is lacking.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

Pakarainen¹,

Ahtiainen²,

Zhang³

et al. 2007

Molecular and Cellular Endocrinology

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Please cite this article as: Pakarainen, T., Ahtiainen, P., Zhang, F.-P., Rulli, S., Poutanen, M., Huhtaniemi, I., Extragonadal LH/hCG action -not yet time to rewrite textbooks, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t AbstractGonadotropins are indispensable in both sexes in the regulation of gonadal sex steroid production and gametogenesis. In addition to their well established classical actions, numerous recent publications have indicated the presence and function of luteinizing hormone/chorionic gonadotropin receptors (LH/hCG-R) in a variety of extragonadal tissues. However, the physiological significance of such effects has remained unclear. We have generated two genetically modified mouse models, one with excessive production of hCG and the other with targeted disruption of LH/hCG-R gene, and used them to address the functions of LH and hCG.Numerous gonadal and extragonadal phenotypes were found in the models with the two extremes of LH/hCG action. However, when the extragonadal effects were scrutinized in greater detail, they all appeared to arise through modification of gonadal function, either through enhanced or inhibited response to LH/hCG stimulation. Hence, further evidence is needed before the extragonadal LH/hCG-R expression can be considered functionally significant.

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“…50,51 When this is taken into consideration along with the incomplete protection of hormone replacement therapy, it is evident that gender-specific, age-related changes in GnRH and the gonadotropic hormones may potentially play a role in the pathogenesis of AD. [52][53][54][55] Supporting a role for LH, as opposed to estrogen, in cognitive decline after menopause, studies have demonstrated that while cognitive decline can be rescued with estrogen therapy initiated immediately after ovariectomy, hormone replacement initiated after a long interval is ineffective.…”

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The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis

Webber¹,

Perry²,

Smith³

et al. 2007

Clinical Medicine & Research

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Al zheimer Disease (AD) is the most prevalent neurodegenerative disease affecting more than 15 million people worldwide 1 and is characterized by selective neuronal degeneration resulting in progressive memory loss. 2 AD attacks several different regions of the brain including the cerebral cortex which is involved in conscious thought and language, the basal forebrain which is important in memory and learning, and the hippocampus which is essential to memory storage. Clinical manifestations of AD are varied but can include memory loss, difficulty performing familiar tasks, disorientation to time and place, misplacing things, and changes in mood or behavior. 3 Several hypotheses have been proposed in attempts to explain the pathogenesis of AD and include theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. 4 The senile plaque, which is primarily composed of the 4.2 kDa amyloid-β polypeptide, is produced from the proteolytic cleavage of the larger amyloid-β precursor protein (AβPP) and is the extracellular hallmark of AD. To date, three genes involving AβPP or its cleavage product have been identified as containing fully penetrant, mutations resulting in early-onset AD. These mutations can be found on genes encoding AβPP itself and also on presenilin-1 and presenilin-2 genes. 5 While these mutations are known to 177 Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. Recent epidemiological and experimental data also support a role for the gonadotropin luteinizing hormone in AD. Paralleling the female predominance for developing AD, luteinizing hormone levels are significantly higher in females as compared to males, and furthermore, luteinizing hormone levels are higher still in individuals who succumb to AD. Luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in AD. Furthermore, we recently examined cognitive performance in a well-characterized transgenic mouse that over-expresses luteinizing hormone and found that these animals show decreased cognitive performance when compared to controls. We have also found that abolishing luteinizing hormone in amyloid-β protein precursor transgenic mice (Tg2576) using a potent gonadotropin-lowering gonadotropin-releasing hormone agonist, leuprolide acetate, resulted in improved hippocampally-related cognitive performance and decreased amyloid-β deposition. These findings, together with data indicating that luteinizing hormone modulates amyloid-β protein precursor p...

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Identification and Structural Characterization of the Neuronal Luteinizing Hormone Receptor Associated with Sensory Systems

Cited by 80 publications

References 52 publications

Luteinizing Hormone Receptor Ectodomain Splice Variant Misroutes the Full-Length Receptor into a Subcompartment of the Endoplasmic Reticulum

Luteinizing Hormone Receptor Ectodomain Splice Variant Misroutes the Full-Length Receptor into a Subcompartment of the Endoplasmic Reticulum

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis

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