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  • Oocytes from the African clawed frog Xenopus laevis have bee


    Oocytes from the African clawed frog Xenopus laevis have been widely used as an expression system to study the modulation of NMDA receptors by metabotropic receptors, such as metabotropic glutamate receptors [12], μ opioid receptors [13], insulin receptors [14] and serotonin receptors [15]. No data are available on the use of this expression system to study the modulation of NMDA receptors by activation of muscarinic receptors. In this study we therefore co-expressed recombinant human muscarinic M1 receptors and human NR1/2B NMDA receptors and assessed if stimulation of the muscarinic M1 receptors by various mAChR agonists resulted in the potentiation of the NMDA responses. Oxotremorine-M is a frequently used mAChR agonist in studies exploring the consequences of muscarinic receptor activation (e.g. [6], [16], [17], [18], [19], [20], [21]). While using oxotremorine-M to study muscarinic modulation of NR1/2B NMDA receptors we found, to our surprise, that besides potentiating NMDA receptors by activation of muscarinic M1 receptors, oxotremorine-M also potentiates NMDA receptors directly by a mechanism that is independent from muscarinic glatiramer acetate receptors.
    Materials and methods
    Discussion In this study we show that the cross-talk between muscarinic acetylcholine M1 receptors and glutamatergic NMDA receptors that occurs in the brain can be reconstituted into a heterologous expression system by co-transfecting both types of neurotransmitter receptors into Xenopus oocytes. This heterologous expression system represents a convenient system to study muscarinic modulation of NMDA receptors. We found, as reported before in native neurons, that activation of muscarinic M1 receptors by various muscarinic receptor agonists results in the potentiation of NMDA receptor-mediated responses. Unexpectedly, we discovered that the frequently used muscarinic receptor agonist oxotremorine-M also potentiated NMDA receptor-mediated ion currents when the muscarinic M1 receptors were fully blocked by the muscarinic receptor antagonist atropine or in oocytes expressing NMDA receptors without muscarinic M1 receptors. These results demonstrate that oxotremorine-M potentiates NMDA receptors also by a second, novel muscarinic receptor-independent mechanism. By co-expressing muscarinic M1 receptors with NR1/2B NMDA receptors in Xenopus oocytes, we showed that it is possible to study muscarinic modulation of NMDA receptors in a heterologous expression system. Modulation of NMDA receptors is not unique to muscarinic M1 receptors, because others have shown that NMDA receptor function can be modulated by various other G-protein coupled receptors that signal via the protein kinase C (PKC) pathway. For example, activation of metabotropic glutamate receptors [12], μ opioid receptors [13], serotonin 5-HT2 receptors [15] and insulin receptors [14] all lead to potentiation of NMDA receptor-mediated ion currents via the common PKC signalling pathway. The diversity of G-protein-coupled receptors linked to the PKC pathway within the nervous system suggests that phosphorylation by PKC is an essential mechanism of fine-tuning the function of NMDA receptors. In addition, different isoforms of NMDA receptor have been shown to have different sensitivities to phosphorylation by PKC. Since the level of NMDA receptor activation is important for processes like synaptic plasticity, induction of long-term potentiation, and also for excitotoxic cell damage, regulation of NMDA receptor function by protein kinases is clearly crucial for the correct functioning of the brain.
    Funding This work was funded by Eli Lilly and Company.
    Conflicts of interest
    Roles of Progesterone Signaling in Various Uterine Compartments during Pregnancy The uterus adopts structural and functional changes in response to hormonal stimulation to prepare for and in support of pregnancy. The uterus is composed of two major compartments, the inner endometrium for embryo implantation and fetal growth and the outer myometrium for structural support and force generation during parturition. During early pregnancy, estrogen promotes proliferation of both luminal and glandular epithelial cells in the endometrium to initiate the preparation for pregnancy. Subsequently, increased progesterone levels (Box 1) and decreased estrogen signaling cease epithelial proliferation and change the composition of a mucinous layer on top of the luminal epithelium cells to allow incoming embryos to contact with the epithelium. At the window of receptivity, a nidatory estrogen surge promotes expression of leukemia inhibitory factor (LIF) in endometrial glands, which alters the cellular junctions between luminal epithelial cells and permits embryos to invade the endometrium. In mice, embryo implantation then elicits the proliferation and differentiation of endometrial stromal cells underneath the epithelium, around the implantation site, to form the decidua that serves as the maternal interface with embryos. Human endometrium, however, exhibits decidualization after ovulation and embryo implantation stimulates further development of decidua (Box 2) [1].