Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.124 Figure 4 Prostaglandin E2 as a gliotransmitter in the gonadotropin-releasing hormone (GnRH) system Figure 4 | Prostaglandin E2 as a gliotransmitter in the gonadotropin-releasing hormone (GnRH) system. In the GnRH system, two different mechanisms, each with different effects on GnRH neuronal activity, control the release of prostaglandin E2 (PGE2). In the first mechanism (left hand side of the figure), the synaptic release of glutamate from the glutamatergic terminal triggers the release of PGE2 by astrocytes via the activation of astrocytic AMPA receptors (AMPARs) and astrocytic metabotropic glutamate receptors (mGluRs)150. The activation of these receptors promotes the recruitment of growth factors, TGFα and neuregulin (NRG), along with their respective receptors, ERBB1 and ERBB4, to the cell membrane of astrocytes150. TGFα and NRG activate ERBB1/ERBB2 and ERBB4/ERBB2 heterodimers, respectively, thereby stimulating the synthesis and release of PGE2 (Ref. 150). In turn, PGE2 acts on PGE2 receptor (PTGER2) located on GnRH-secreting neurons, which leads to the activation of a non-selective cation channel (NSCC) through a cAMP/protein kinase A (PKA)-dependent pathway170. Cation influx through the NSCC induces membrane depolarization and increases firing of GnRH-secreting neurons170. In the second mechanism (right hand side of the figure), glutamate released from depolarized (ΔVm) GnRH-secreting neurons triggers the release of PGE2 from astrocytes159. Membrane depolarization of GnRH-secreting neurons (ΔVm) also induces the release of endocannabinoids159. Glutamate and endocannabinoids activate presynaptic mGluRs and cannabinoid receptor 1 (CB1), respectively, to inhibit the release of GABA, which acts on the postsynaptic GABAA receptor (GABAAR)159. Given that GABA is an excitatory neurotransmitter in the GnRH system, this provides a negative feedback loop in which depolarized GnRH-secreting neurons reduce their own activity by inhibiting the activity of excitatory GABAergic inputs. PGE2 released by astrocytes following activation of mGluR can then act postsynaptically and presynaptically to increase endocannabinoid synthesis and CB1 trafficking, respectively, potentiating this local inhibitory feedback circuit159. Clasadonte, J. & Prevot, V. (2017) The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.124