Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (Ghrhr^Gpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic Ghrhr^Gpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only G_s, but also G_q/11 and G_12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.

Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors have been reported, no such ligands are available for KARs. In this study, we investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM344) potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 μM), with an EC₅₀ of 79 μM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. 4-cyclopropyl-7-hydroxy-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM521) potentiated the recorded peak current amplitude of GluK2a 12-fold at a concentration of 300 μM with an EC₅₀ value of 159 μM, whereas no potentiation of the glutamate-evoked response was observed for 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM121) at the highest concentration of modulator tested (300 μM). BPAM344 (100 μM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15-fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1_i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator-binding sites at the GluK1 dimer interface. In conclusion, this study may enable the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigation of the function of KARs in vivo and may prove useful for pharmacologically controlling the activity of neuronal networks.

The real impact of polyphenol-rich vegetable and fruit juice intake on cardiovascular health remains a matter of controversy. In the present study, rat aorta segments immersed in an organ bath (OB) were used to explore whether the total polyphenol content and/or individual phenolic compound contents of 22 commercial vegetable (n = 3) and fruit juices [(citrus (n = 5), berries (n = 10), apple (n = 2), pineapple (n = 2)] might be associated with vascular tone. Red juices (particularly blackcurrant) and lemon juice caused the most marked vasorelaxation, its amplitude being endothelium dependent or not according to the volume ratio of juice to initial OB solution V_juice/V_OBS). At volume ratios 5% and 10%, both the juice and OB total polyphenol for all juices and total anthocyanin contents for berry juices significantly correlated with aorta vasorelaxation intensity. This was not the case for total or individual flavonols (except kaempferol) or for total or individual flavanols (except epigallocatechin gallate). If one relates our measured concentrations of individual phenolic compounds in OB to what is known about their physiological concentrations, and given our evidenced correlations between compound concentrations and vasorelaxation intensity, kaempferol, epigallocatechin gallate and peonidin-3-O-glucoside seem to emerge as the interesting phenolic compounds likely to be responsible for the potent vasorelaxation observed with fruit juices, and more particularly blackcurrant ones. Clinical investigation is required, however, to confirm our observations.