Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors
Abstract
:1. Introduction
2. LHR and FSHR Structure and Function
2.1. Luteinizing Hormone Receptors (LHRs)
2.2. Follicle Stimulating Hormone Receptors (FSHRs)
3. LH, hCG, and FSH Structures
4. Initiation of Signal Transduction: Effects of Receptor Aggregation on Receptor Function
Receptor | Cell Type/Tissue | Experimental Method (s) | Probe (s) | Result | Ref. |
---|---|---|---|---|---|
Rat LHRs | Granulosa cells | Formaldehyde fixation/light microscopy/autoradiography | Rabbit anti-hCG/FITC-goat anti rabbit IgG | hCG treatment produced small LHR clusters at 4 °C, larger clusters at 37 °C | [52] |
Rat LHRs | Rat luteal cells | Electron microscopy | Ferritin-LH (FE-LH) | FE-LH treated LHR clusters at 37 °C | [53] |
Porcine LHRs | Porcine granulosa cells | Fluorescence resonance energy transfer (FRET) measured using spectrofluorimetry | FITC-/TrITC-hCG or FITC-/TrITC-hCG | Positive FRET (4 °C) for LH and hCG probes. LH: Reduced FRET (37 °C), hCG: minimal FRET (37 °C) | [54] |
Rat LHRs | CHO cells | Fluorescence recovery after photobleaching (FRAP) | LHR-GFP (C-terminus) | LH reduced the fraction of mobile LHRs at 37 °C. hCG produced visible, immobile LHR clusters | [55] |
Rat LHRs | CHO cells | Fluorescence recovery after photobleaching (FRAP) | LHR-GFP (C-terminus) | hCG increases LHR clusters which must dissipate before receptors can signal | [56] |
FRET | LHR-GFP/LHR-YFP | Immobile LHR clusters exhibit increased FRET | |||
Porcine LHRs | Porcine follicle membranes | Confocal microscopy | TrITC-hCG | Active: LHRs in small clusters Desensitized: LHRs in large clusters | [46] |
Time-resolved phosphorescence anisotropy | ErITC-hCG | Active: Small clusters, faster rotational correlation times Desensitized: larger clusters, slower rotational correlation times | |||
FRET | FITC-hCG/TrITC-hCG | Active: Less FRET Desensitized: Increased FRET | |||
Human LHRs | HEK 293 | Co-immunoprecipitation | c-myc-LHR (N-terminus)/ FLAG-LHR (N-terminus) | Coprecipitation of high molecular weight complexes from cells stably expressing LHRs. No detected change in complex molecular weight with hCG treatment. | [48] |
Human LHRs | HEK 293 | Fluorescence cross-correlation spectroscopy (FCCS) | hLHRs-delExon10–GFP/hLHR-C131R–mCherry; hLHR-K605E–GFP/hLHR-C131R–mCherry | FCCS showed cross-correlation for each receptor combination. Trans-activation partially rescued hCG response (increased cAMP) but not LH response | [13] |
Rat LHRs | HEK 293 | PALM super-resolution imaging | HA-WT-LHR, HA-LHRB-, FLAG-LHRS- (HA.11/FLAG Abs) | WT alone and LHRB- + LHRS- exhibited intermolecular interactions favoring the formation of LHR oligomers | [57] |
Human FSHRs | HEK 293 | Imaging FRET | Anti-FSHR mAb-Alexa 588/Anti-FSHR An-Alexa 647 | Positive FRET for untreated/FSH-treated FSHRs | [18] |
Co-immunoprecipitation | c-Myc-FSHR FLAG-FSHR | FSH oligomers form early in FSHR biosynthesis | |||
Human FSHRs | X-ray Crystallography | Asna52-FSH or fully glycosylated FSH | FSHRs are a functional trimer when binding Asna52-FSH | [58] | |
Human FSHRs | HEK293 | Fluorescence correlation spectroscopy/photon counting histogram analysis | Chimeric human-FSHR with rat LHR C terminus-EGFP | Human FSHR/LHR C-terminus chimeras are homodimers | [50] |
5. LHRs and FSHRs in Disease
Receptor/Mutation | Homozygous/HeteRozygous | Phenotype | Reference |
---|---|---|---|
Follicle Stimulating Hormone Receptor | |||
S128Y(T) | Spontaneous ovarian hyperstimulation syndrome during pregnancy, increased hCG, TSH response | [88] | |
I61N | Heterozygous | Amenorrhea, infertility, early antral follicles, no cAMP | [89] |
T449A | Spontaneous ovarian hyperstimulation syndrome during pregnancy, increased hCG, TSH response | [90] | |
T449I | Spontaneous ovarian hyperstimulation syndrome during pregnancy, increased hCG, TSH response | [90] | |
P519T | Failure of FSH to bind to FSHRs, hypergonadism | [91] | |
D567N | Spontaneous ovarian hyperstimulation syndrome during pregnancy, increased hCG, TSH response, impaired FSHR desensitization, hypogonadotropic hypogonadism, precocious pseudopuberty | [90] | |
N680S | Homozygous | PCOS, premature ovarian syndrome, high circulating FSH, decreased FSHR activity | [92] |
P688T | Heterozygous | Amenorrhea, infertility, early antral follicles, decreased cAMP | [63] |
Luteinizing Hormone Receptor | |||
L10P | Signal peptide mutation causing micropenis, cryptorchidism | [93] | |
Q18-L19ins9 | Signal peptide mutation causing severe Leydig cell hypoplasia | [94] | |
I114F | Heterozygous | XY disorder of sexual development (XY DSD), Leydig cell hypoplasia, decreased LHRs, reduced signal transduction | [95] |
C131R | Homozygous | Impaired cAMP response, micropenis, hypospadias, Hypoplastic phallus with hypospadias, XY DSD | [96] |
V144F | homozygous | XY DSD | [97] |
I152T | No Leydig cells, immature seminiferous tubules, impaired hormone binding, signal, genitalia with some virilization | [98] | |
Q170Stop | Homozygous | Nonsense mutation causing primary amenorrhea | [99] |
F194V | XY DSD, no cAMP signal | [100] | |
N312S | Homozygous | Leydig cell hypoplasia in males and higher success rates for IVF pregnancy in females | [101] |
Deletion between Y317 and S324 | Homozygous | Hypergonadism in males and Primary and secondary amenorrhea in females | [102] |
Y317-S324 deletion | Homozygous | Males: Splice site mutation causing micropenis, delayed puberty, oligospermia Females: infertility with/without oligomenorrhea in females | [64] |
C343S | Compound heterozygote | XY DSD | [103] |
E354K | Homozygous | XY DSD, undescended testes in males and primary amenorrhea in females | [104] |
L368P | Missense mutation causing precocious puberty, increased cAMP * | [105] | |
I374T | Heterozygous | XY DSD, Leydig cell hypoplasia | [106] |
T392I | Double homozygote | XY DSD, Leydig cell hypoplasia | [106] |
M398T | Heterozygous | Familial male limited precocious puberty * | [107] |
N400S | Homozygous | Infertility, empty follicle syndrome | [108] |
I415T | Heterozygous | Leydig cell hypoplasia, micropenis, no cAMP production | [109] |
L457R | Elevated cAMP, precocious puberty * | [12] | |
T461I, exon 6A mutation | Compound heterozygote | XY DSD | [110] |
L502P | XY DSD, Leydig cell hypoplasia | [111] | |
Q525Stop | homozygous | Primary amenorrhea | [99] |
I528Stop | Heterozygous | Leydig cell hypoplasia | [112] |
I542L | Familial male limited precocious puberty * | [67] | |
C543R | Compound heterozygote | XY DSD | [103] |
C545Stop | Heterozygous | No cAMP, XY DSD | [113] |
R554Stop | Homozygous | Males: XY DSD Females: small uterus, cystic ovary, primary and secondary amenorrhea | [114] |
D564G | Heterozygous | Familial male limited precocious puberty * | [115] |
A568V | Homozygous | Precocious puberty * | [105] |
I575L | Heterozygous | Familial male limited precocious puberty * | [107] |
D578G (H, E, Y) | Familial male precocious puberty, Leydig cell hyperplasia, precocious puberty * | [65,66,116,117,118,119] | |
A593P | Homozygous | XY DSD, Leydig cell hypoplasia in males and primary amenorrhea, lack of breast development, infertility in females | [96] |
I625K | Homozygous | Micropenis, no puberty, infertility | [96] |
Exon 8 and S616Y deletion | Compound heterozygote | Leydig cell hypoplasia, micropenis, hypospadias | [120] |
Exon 10 deletion | Homozygous | Hypogonadism, no puberty | [121] |
6. Turning the Signaling by Membrane-Expressed LHR Receptors on or off
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
LHR | Luteinizing hormone receptor |
FSHR | follicle-stimulating hormone receptor |
GPCR | G protein-coupled receptor |
LH | luteinizing hormone |
FSH | follicle-stimulating hormone |
hCG | human chorionic gonadotropin |
DG | deglycosylated human chorionic gonadotropin |
COS | polycystic ovary disease |
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Althumairy, D.; Zhang, X.; Baez, N.; Barisas, G.; Roess, D.A.; Bousfield, G.R.; Crans, D.C. Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors. Diseases 2020, 8, 35. https://doi.org/10.3390/diseases8030035
Althumairy D, Zhang X, Baez N, Barisas G, Roess DA, Bousfield GR, Crans DC. Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors. Diseases. 2020; 8(3):35. https://doi.org/10.3390/diseases8030035
Chicago/Turabian StyleAlthumairy, Duaa, Xiaoping Zhang, Nicholas Baez, George Barisas, Deborah A. Roess, George R. Bousfield, and Debbie C. Crans. 2020. "Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors" Diseases 8, no. 3: 35. https://doi.org/10.3390/diseases8030035
APA StyleAlthumairy, D., Zhang, X., Baez, N., Barisas, G., Roess, D. A., Bousfield, G. R., & Crans, D. C. (2020). Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors. Diseases, 8(3), 35. https://doi.org/10.3390/diseases8030035