Signaling by G-protein-coupled receptor (GPCR): Studies on the GnRH receptor

Abundant evidences have shown that ghrelin, by its binding to GHS-R1a, plays an important role for fundamental physiological functions. Increasing attention is given to the GHS-R1a unusually high constitutive activity and its contribution to downstream signalling and physiological processes. Here, we review recent lines of evidences showing that the interaction between ligand-binding pocket TM domains and the ECL2 could be partially responsible for this high constitutive activity. Interestingly, GHSR-1a constitutive activity activates in turn the downstream PLC, PKC and CRE signalling pathways and this activation is reversed by the inverse agonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P (MSP). Noteworthy, GHSR-1a exhibits a C-terminal-dependent constitutive internalization. Non-sense GHS-R1a mutation (Ala204Glu), first discovered in Moroccan patients, supports the role of GHSR-1a constitutive activity in physiological impairments. Ala204Glu-point mutation, altering exclusively the GHSR-1a constitutive activity, was associated with familial short stature syndrome. Altogether, these findings suggest that GHS-R1a constitutive activity could contribute to GH secretion or body weight regulation. Consequently, future research on basic and clinical applications of GHS-R1a inverse agonists will be challenging and potentially rewarding.

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GHS-R1a constitutive activity and its physiological relevance.

The effects of rottlerin, a known inhibitor of protein kinase C-δ activation, on ion currents were investigated in pituitary tumor (GH3) cells. Rottlerin (0.3–100 µM) increased the amplitude of Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 1.7 µM. In intracellular perfusion with rottlerin (1 µM) or staurosporine (10 µM), phorbol 12-myristate 13-acetate-induced inhibition of IK(Ca) in these cells was abolished. In cell-attached mode, rottlerin applied on the extracellular side of the membrane caused activation of large-conductance Ca2+-activated K+ (BKCa) channels, and a further application of BAPTA-AM (10 µM) to the bath had no effect on rottlerin-stimulated channel activity. When cells were exposed to rottlerin, the activation curve of these channels was shifted to less positive potential with no change in the slope factor. Rottlerin increased BKCa-channel activity in outside-out patches. Its change in kinetic behavior of BKCa channels is primarily due to an increase in mean open time. With the aid of minimal kinetic scheme, a quantitative description of rottlerin stimulation on BKCa channels in GH3 cells was also provided. Under current-clamp configuration, rottlerin (1 µM) decreased the firing of action potentials. IK(Ca) elicited by simulated action potential waveforms was enhanced by this compound. In human cortical HCN-1A cells, rottlerin (1 µM) could also interact with the BKCa channel to stimulate IK(Ca). Therefore, rottlerin may directly activate BKCa channels in neurons or endocrine cells. J. Cell. Physiol. 210: 655–666, 2007. © 2006 Wiley-Liss, Inc.

Potent stimulation of large-conductance Ca2+-activated K+ channels by rottlerin, an inhibitor of protein kinase C-δ, in pituitary tumor (GH3) cells and in cortical neuronal (HCN-1A) cells

Nonfunctioning pituitary adenomas (NFPA; gonadotroph derived), even not inducing hormonal hypersecretion, cause significant morbidity by compression neighboring structures. No effective and specific medical methods are available so far for treating these tumors. The pituitary homeobox 2 (PITX2) gene is a member of the bicoid-like homeobox transcription factor family, which is involved in the Wnt/Dvl/β-catenin pathway. PITX2 is overexpressed in NFPA. PITX2 mutations are known to be responsible for Axenfield Rieger syndrome, a genetic disorder in which pituitary abnormalities have been detected. The R91P mutant identified in Axenfeld Rieger syndrome is a dominant-negative factor, which is able to block the expression of several pituitary genes activated by PITX2. To better understand the role of Pitx2 on gonadotroph tumorigenesis and to explore new approach for inhibiting tumoral growth, the R91P mutant was transferred via a lentiviral vector in tumoral gonadotroph cells of two kinds: the αT3-1 cell line and human adenoma cells. R91P mutant and small interfering RNA directed against Pitx2 both decreased the viability of αT3-1 cells via an apoptotic mechanism involving the activation of executioner caspase. Similar effects of the R91P mutant were observed on human gonadotroph cells in primary culture. Therefore, Pitx2 overexpression may play an antiapoptotic role during NFPA tumorigenesis.

Inactivation of PITX2 Transcription Factor Induced Apoptosis of Gonadotroph Tumoral Cells

Differential roles of PKC isoforms (PKCs) in GnRH stimulation of MAPK phosphorylation in gonadotrope derived cells.

We investigated the kinetics of gonadotropin-releasing hormone (GnRH)-induced activation of the protein kinase C (PKC) δ isoform in αT3-1 gonadotrope cells. Results were evaluated in subcellular fract

Protein Kinase Cδ as Gonadotropin-Releasing Hormone Target Isoenzyme in the αT3-1 Gonadotrope Cell Line

Background/Aim: Protein kinase C (PKC) is a family of isoenzymes playing a key role in the regulation of gonadotrope cell functions. Specific PKC isoforms are activated and downregu

Ubiquitination as a priming process of PKC alpha and PKC epsilon degradation in the alphaT3-1 gonadotrope cell line

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Protein Kinase Cδ as Gonadotropin-Releasing Hormone Target Isoenzyme in the αT3-1 Gonadotrope Cell Line

Ubiquitination as a priming process of PKC alpha and PKC epsilon degradation in the alphaT3-1 gonadotrope cell line