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.

/pdf/ghs-r1a-constitutive-activity-and-its-physiological-g3c8vmvyla.pdf

GHS-R1a constitutive activity and its physiological relevance.

Previous studies have shown that the Epstein-Barr virus-encoded latent membrane protein1 (LMP1) could activate nuclear factor kappa B, activator protein-1, and Janus kinases/signal transducer and activation of transcription factors pathways. However, many signaling molecules and downstream target proteins triggered by LMP1 have not been identified. To determine the functional components in signaling pathways triggered by LMP1, we combined the novel strategy of phosphoprotein enrichment with proteomics technology to elucidate the signaling cascade activated by LMP1. We found that LMP1 could increase the quantity of total phosphoproteins by 18.03%, and 43 proteins showed significant changes in the degree of phosphorylation when LMP1 was expressed. Twenty-five signaling molecules or downstream targets of signaling pathways triggered by LMP1 were identified, several of which had previously been implicated in LMP1 signal pathways. The other proteins, including annexin A2, heat shock protein 27, stathmin, annexin I, basic transcription factor 3, and porin, were novel signaling molecules or targets with no previously known function in LMP1 signal transduction. The method used here has proven to be suitable for the identification of molecules involved in various signaling pathways.

Identification of novel phosphoproteins in signaling pathways triggered by latent membrane protein 1 using functional proteomics technology.

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

The phosphoprotein stathmin exerts profound influences on cell proliferation, differentiation and in cell motility. These phenotypic features are displayed in response to specific signals imparted to the cell by biological response modifiers. Stathmin functions as a focal point in co-ordinating and directing the cellular signals into specific and defined pathways. Two biological features that characterise cancer are the deregulation of cell proliferation leading to tumour growth and invasive behaviour. Stathmin is up-regulated in many neoplasms and the modulation of its expression correlates with invasion and metastasis and highly proliferating normal tissues. The integrity of the transduction of extracellular signals is essential for the normal functioning of the cellular machinery in cell differentiation, morphogenesis and cell proliferation, apoptosis, growth and senescence. Stathmin mediates these pathways of signalling. Stathmin has been implicated in both G1-S and G2-M checkpoint control of cell cycle progression by influencing the dynamics of microtubule formation and progression of the cell cycle. Stathmin appears to exert its regulatory effects at both G1-S and G2-M checkpoints by interacting with other cell cycle control proteins such as p53 and rb and with cancer metastasis promoting or inhibiting genes as well as other proteins such as heat shock proteins. Stathmin co-ordinates the signalling by extracellular matrix proteins, and defines intercellular adhesion and cell motility. Therefore, the deregulation of stathmin function would have profound implications in the pathogenesis and progression of cancer.

Stathmin in Cell Proliferation and Cancer Progression

We have investigated the effects of GnRH (LHRH) and of the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate on stathmin phosphorylation in the gonadotrope alphaT3-1 cell line. Stathmin expression and its phosphorylation were maximal during the exponential phase of cell growth. LHRH stimulated stathmin phosphorylation through a specific receptor in a dose- and time-dependent manner, and TPA induced a similar extensive stathmin phosphorylation. Their effects were inhibited either in PKC-depleted alphaT3-1 cells, or by the PKC inhibitor staurosporine. In the context of the known implication of PKC in LHRH-induced signal transduction, our results show that stathmin phosphorylation is involved in LHRH transduction, either as a result of direct activation of specific PKC isoforms or through a pathway involving kinases downstream to PKC activation.

/pdf/luteinizing-hormone-releasing-hormone-signal-transduction-4hiyupdbkr.pdf

Luteinizing hormone-releasing hormone-signal transduction and stathmin phosphorylation in the gonadotrope alphaT3-1 cell line.

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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Luteinizing hormone-releasing hormone-signal transduction and stathmin phosphorylation in the gonadotrope alphaT3-1 cell line.

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