Activation of MAPK Cascades by G-protein-coupled Receptors: The Case of Gonadotropin-releasing Hormone Receptor

Naor, Zvi; Benard, Outhiriaradjou; Seger, Rony

doi:10.1016/s1043-2760(99)00232-5

Cited by 310 publications

(255 citation statements)

References 77 publications

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“…In most cells, activation of ERK by GPCRs and via PKC is Ca 2ϩ -dependent (37,38), whereas we present evidence here that activation of spermatozoan ERK by PMA is Ca 2ϩ -independent. Mammalian spermatozoa express the G-protein G q , phospholipase C␣, and inositol 1,4,5-trisphosphate receptors (39,40).…”

Section: Discussioncontrasting

confidence: 64%

Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Almog

Lazar

Reiss

et al. 2008

Journal of Biological Chemistry

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106

127

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Mature spermatozoa acquire progressive motility only after ejaculation. Their journey in the female reproductive tract also includes suppression of progressive motility, reactivation, capacitation, and hyperactivation of motility (whiplash), the mechanisms of which are obscure. MAPKs are key regulatory enzymes in cell signaling, participating in diverse cellular functions such as growth, differentiation, stress, and apoptosis. Here we report that ERK1/2 and p38 MAPK are primarily localized to the tail of mature human spermatozoa. Surprisingly, c-Jun N-terminal kinase 1/2, which is thought to be ubiquitously expressed, could not be detected in mature human spermatozoa. ERK1/2 stimulation is downstream to protein kinase C (PKC) activation, which is also present in the human sperm tail (PKC␤I and PKC⑀). ERK1/2 stimulates and p38 inhibits forward and hyperactivated motility, respectively. Both ERK1/2 and p38 MAPK are involved in the acrosome reaction. Using a proteomic approach, we identified ARHGAP6, a RhoGAP, as an ERK substrate in PMA-stimulated human spermatozoa. Inverse correlation was obtained between the relative expression level of ERK1 or the relative activation level of p38 and sperm motility, forward progression motility, sperm morphology, and viability. Therefore, increased expression of ERK1 and activated p38 can predict poor human sperm quality.

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Section: Discussioncontrasting

confidence: 64%

Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Almog

Lazar

Reiss

et al. 2008

Journal of Biological Chemistry

Self Cite

106

127

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“…This process together with the massive entry of Ca 2+ that occurs through voltage-dependent or -independent channels [27] is primarily involved in acute gonadotropin release. GnRH can also induce the activation of the mitogen associated protein kinase (MAPK) cascade through PKC to stimulate the expression of gonadotropin subunit genes [28,29]. Elevation of intracellular Ca 2+ also activates the NO synthase (NOS I) cascade (NOS I/NO/soluble guanylate cyclase) that results in the rapid production of cGMP [30,31], providing another example of an indirectly activated signalling pathway.…”

Section: Gnrh Receptor Signallingmentioning

confidence: 99%

Gonadotropin-releasing hormone and the control of gonadotrope function

et al. 2005

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-Normal gametogenesis and steroidogenesis is highly dependent on the pulsatile release of hypothalamic GnRH that binds high-affinity receptors present at the surface of pituitary gonadotrophs thereby triggering the synthesis and release of the gonadotropins LH and FSH. The mammalian GnRH receptor displays the classical heptahelical structure of G protein-coupled receptors with, however, a unique feature, the lack of a C-terminal tail. Accordingly, it does not desensitise sensu stricto, and internalises very poorly. It is now well established that GnRH stimulation induces the activation of a complex network of transduction pathways involved in the control of gonadotropin release and subunit gene expression. Other authors and ourselves have demonstrated that the GnRH action is associated with an increased complexity regarding gene regulation/cell function. Indeed GnRH affects the GnRH receptor gene itself and a number of additional genes that include some involved in cell signalling and auto-/paracrine regulation. The fact that GnRH regulates the expression of its own receptor, together with a host of other genes typically involved in its signal transduction cascades implies alteration/auto-adaptation in gonadotropic responsiveness. Furthermore, some of these genes respond differentially depending on whether the GnRH stimulation is intermittent or permanent suggesting specific roles in the dual process of activation/desensitisation. Thus, it can be assumed that the importance of pulsatility of GnRH action is closely related to, or dependent on, the inability of the GnRH receptor to desensitise. Moreover, multiple post-receptor events are crucial for both the regulation/plasticity of gonadotropic function and the maintenance of cell integrity.

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“…Although the Geoffrey Harris lecture painted a broad canvas covering a wide spectrum of GnRH research, some of these areas (such as intracellular signaling, GnRH receptors and GnRH analogs) have been the subject of extensive and recent review [39,58,83,86,87,95,104,105,126,135] and will not be reiterated in detail in this article. We would instead focus on three extra-pituitary features of GnRH action.…”

Section: Introductionmentioning

confidence: 99%

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

Millar

Pawson

Morgan

et al. 2008

Frontiers in Neuroendocrinology

122

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Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G q signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.

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Activation of MAPK Cascades by G-protein-coupled Receptors: The Case of Gonadotropin-releasing Hormone Receptor

Cited by 310 publications

References 77 publications

Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality

Gonadotropin-releasing hormone and the control of gonadotrope function

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

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