Abstract
Glucocorticoids induce a rapid synthesis of endocannabinoid in hypothalamic neuroendocrine cells by activation of a putative membrane receptor. Somato-dendritically released endocannabinoid acts as a retrograde messenger to suppress excitatory synaptic inputs to corticotropin-releasing hormone-, oxytocin-, and vasopressin-secreting cells. The non-genomic signaling mechanism responsible for rapid endocannabinoid synthesis by glucocorticoids has yet to be fully characterized. Here we manipulated cell signaling molecules pharmacologically using an intracellular approach to elucidate the signaling pathway activated by the membrane glucocorticoid receptor in hypothalamic neuroendocrine cells. We found that rapid glucocorticoid-induced endocannabinoid synthesis in magnocellular neuroendocrine cells requires the sequential activation of multiple kinases, phospholipase C, and intracellular calcium mobilization. While there remain gaps in our understanding, our findings reveal many of the critical players in the rapid glucocorticoid signaling that culminates in the retrograde endocannabinoid modulation of excitatory synaptic transmission.
Highlights
Endocannabinoids are endogenous analogues of the plant-derived cannabinoid Δ9 tetrahydrocannabinol that act at cannabinoid receptors
We demonstrated that the glucocorticoids dexamethasone (Dex) and corticosterone (Cort) cause a significant decrease in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in magnocellular and parvocellular neuroendocrine cells of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) by stimulating the synthesis and release of a retrograde endocannabinoid messenger (Di et al, 2003; Malcher-Lopes et al, 2006)
We present evidence from pharmacological analyses in brain slices of a complex signaling pathway downstream from a membrane glucocorticoid receptor that stimulates the synthesis and release of the endocannabinoid 2-AG, which leads to the suppression of excitatory synaptic transmission in hypothalamic magnocellular neurons
Summary
Endocannabinoids are endogenous analogues of the plant-derived cannabinoid Δ9 tetrahydrocannabinol that act at cannabinoid receptors. Endocannabinoids can be produced transiently by strong postsynaptic depolarization and calcium influx through voltage-gated calcium channels (Maejima et al, 2001; OhnoShosaku et al, 2002) and in response to synaptic activity (Azad et al., 2004; Chevaleyre and Castillo, 2003; Chiu et al, 2010; Di et al, 2005a) and G protein-coupled receptor activation linked to phospholipase C (PLC) signaling (Kano et al, 2009; Maejima et al, 2001; Varma et al, 2001). Group 1 metabotropic glutamate receptors or muscarinic acetylcholine receptors linked to PLC converge with calcium signaling mechanisms to decrease the threshold for endocannabinoid synthesis (Hashimotodani et al, 2005; Ohno-Shosaku et al, 2002). CAMP-dependent protein kinase (PKA) and protein kinase C (PKC) have both been implicated in endocannabinoid production (Cadas et al, 1996; De Petrocellis et al, 2008), the specific role of kinase activity in endocannabinoid release has yet to be fully elucidated
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