Cell signaling dependence of rapid glucocorticoid-induced endocannabinoid synthesis in hypothalamic neuroendocrine cells

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.

Acute Stress Desensitizes Hypothalamic CRH Neurons to Norepinephrine and Physiological Stress

“…Nevertheless, the effect of the steroid was lost in CRH neurons from GR knockout mice, which suggests that it is dependent on the nuclear GR. We have reported a rapid glucocorticoid-induced endocannabinoid suppression of excitatory synapses in PVN CRH neurons and magnocellular neurons that is also dependent on the GR, but does not require gene transcription and is mediated by an intracellular signaling cascade 22,25,26,42 . The rapid glucocorticoid suppression of excitatory synaptic inputs was also observed here, and was also reversed in CRH neurons from GR knockout mice.…”

“…The rapid glucocorticoid suppression of excitatory synaptic inputs was also observed here, and was also reversed in CRH neurons from GR knockout mice. It is reasonable to envision the membrane transduction mechanism responsible for the rapid glucocorticoid regulation of α 1 receptor trafficking in CRH neurons as the same as or as a branch of the membrane glucocorticoid receptor signaling mechanism that leads to endocannabinoid synthesis at glutamate synapses 42 44 and hippocampal dentate gyrus 45 . Serum-and glucocorticoid-inducible kinase (SGK), guanosine nucleotide dissociation inhibitor (GSI), and Rab family small-molecule G proteins were reported to mediate the corticosterone regulation of AMPA receptor trafficking in the prefrontal cortex 31,46 .…”

Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?

“…The synergy spreads across the rapid and slow temporal domains of glucocorticoid actions (Figure 1). Indeed, glucocorticoids use a yet to be identified membrane‐bound receptor to promote endocannabinoid secretion that suppresses neurotransmitter release from the presynaptic terminals 65 . This way, the rapid effects could transform the slow effects compared to what might have been expected in absence of neural activity and neurotransmitter release.…”

Meet Your Stress Management Professionals: The Endocannabinoids

“…Concentrations of both of the eCBs are regulated by stress (Figure 2B). Recent studies indicate that GCs rapidly increase synaptic concentrations of 2-AG through membranelocalized glucocorticoid receptors coupled to 2-AG synthesis [12], directly linking HPA axis activation to increased 2-AG. AEA concentrations are also altered by stress exposure, although stress regulates AEA catabolism rather than synthesis.…”