guanosine-triphosphate has been researched along with Hypogonadism* in 2 studies
2 other study(ies) available for guanosine-triphosphate and Hypogonadism
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Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation.
RAB18, RAB3GAP1, RAB3GAP2 and TBC1D20 are each mutated in Warburg Micro syndrome, a rare autosomal recessive multisystem disorder. RAB3GAP1 and RAB3GAP2 form a binary 'RAB3GAP' complex that functions as a guanine-nucleotide exchange factor (GEF) for RAB18, whereas TBC1D20 shows modest RAB18 GTPase-activating (GAP) activity in vitro. Here, we show that in the absence of functional RAB3GAP or TBC1D20, the level, localization and dynamics of cellular RAB18 is altered. In cell lines where TBC1D20 is absent from the endoplasmic reticulum (ER), RAB18 becomes more stably ER-associated and less cytosolic than in control cells. These data suggest that RAB18 is a physiological substrate of TBC1D20 and contribute to a model in which a Rab-GAP can be essential for the activity of a target Rab. Together with previous reports, this indicates that Warburg Micro syndrome can be caused directly by loss of RAB18, or indirectly through loss of RAB18 regulators RAB3GAP or TBC1D20. Topics: Abnormalities, Multiple; Animals; Blotting, Western; Case-Control Studies; Cataract; Cells, Cultured; Cornea; Cytosol; Endoplasmic Reticulum; Fibroblasts; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation; Guanosine Triphosphate; HeLa Cells; Humans; Hydrolysis; Hypogonadism; Intellectual Disability; Mice; Mice, Knockout; Microcephaly; Optic Atrophy; rab GTP-Binding Proteins; rab1 GTP-Binding Proteins; rab3 GTP-Binding Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger | 2015 |
Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function.
The G-protein-coupled receptor (GPCR) GPR54 is essential for the development and maintenance of reproductive function in mammals. A point mutation (L148S) in the second intracellular loop (IL2) of GPR54 causes idiopathic hypogonadotropic hypogonadism, a disorder characterized by delayed puberty and infertility. Here, we characterize the molecular mechanism by which the L148S mutation causes disease and address the role of IL2 in Class A GPCR function. Biochemical, immunocytochemical, and pharmacological analysis demonstrates that the mutation does not affect the expression, ligand binding properties, or protein interaction network of GPR54. In contrast, diverse GPR54 functional responses are markedly inhibited by the L148S mutation. Importantly, the leucine residue at this position is highly conserved among class A GPCRs. Indeed, mutating the corresponding leucine of the alpha(1A)-AR recapitulates the effects observed with L148S GPR54, suggesting the critical importance of this hydrophobic IL2 residue for Class A GPCR functional coupling. Interestingly, co-immunoprecipitation studies indicate that L148S does not hinder the association of Galpha subunits with GPR54. However, fluorescence resonance energy transfer analysis strongly suggests that L148S impairs the ligand-induced catalytic activation of Galpha. Combining our data with a predictive Class A GPCR/Galpha model suggests that IL2 domains contain a conserved hydrophobic motif that, upon agonist stimulation, might stabilize the switch II region of Galpha. Such an interaction could promote opening of switch II of Galpha to facilitate GDP-GTP exchange and coupling to downstream signaling responses. Importantly, mutations that disrupt this key hydrophobic interface can manifest as human disease. Topics: Amino Acid Motifs; Amino Acid Substitution; Cell Line; Genetic Diseases, Inborn; GTP-Binding Protein alpha Subunits; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Hydrophobic and Hydrophilic Interactions; Hypogonadism; Point Mutation; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1 | 2008 |