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Stress responses: the contribution of prostaglandin E2 and its receptors

Nature Reviews Endocrinology volume 7, pages 163–175 (2011)Cite this article

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Abstract

Stress is a state of physiological or psychological strain caused by adverse stimuli; responses to stress include activation of the sympathetic nervous system, glucocorticoid secretion and emotional behaviors. Prostaglandin E2 (PGE2), acting through its four receptor subtypes (EP1, EP2, EP3 and EP4), is involved in these stress responses. Studies of EP-selective drugs and mice lacking specific EPs have identified the neuronal pathways regulated by PGE2. In animals with febrile illnesses, PGE2 acts on neurons expressing EP3 in the preoptic hypothalamus. In illness-induced activation of the hypothalamic–pituitary–adrenal axis, EP1 and EP3 regulate distinct neuronal pathways that converge at the paraventricular hypothalamus. During psychological stress, EP1 suppresses impulsive behaviors via the midbrain dopaminergic systems. PGE2 promotes illness-induced memory impairment, yet also supports hippocampus-dependent memory formation and synaptic plasticity via EP2 in physiological conditions. In response to illness, PGE2 is synthesized by enzymes induced in various cell types inside and outside the brain, whereas constitutively expressed enzymes in neurons and/or microglia synthesize PGE2 in response to psychological stress. Dependent on the type of stress stimuli, PGE2 released from different cell types activates distinct EP receptors, which mobilize multiple neuronal pathways, resulting in stress responses.

Key Points

  • Prostaglandin E2 (PGE2) regulates multiple responses to illness and psychological stress via distinct PGE receptor subtypes (EP1, EP2, EP3 and EP4)

  • During illness-induced fever, PGE2 activates EP3 in neurons in the preoptic hypothalamus, which promotes two independent effector mechanisms: heat production in brown adipose tissue and vasoconstriction of the skin

  • In illness-induced activation of the hypothalamic–pituitary–adrenal axis, EP1 and EP3 mediate distinct neuronal pathways that converge on neurons in the paraventricular hypothalamus that contain corticotropin-releasing factor

  • Under psychological stress, the PGE2–EP1 signaling pathway regulates impulsive behaviors via the midbrain dopaminergic system

  • PGE2 regulates illness-induced impairment of memory formation, but under physiological conditions (without illness), it supports hippocampus-dependent memory formation and synaptic plasticity via EP2

  • PGE2 is synthesized by enzymes induced inside and outside the brain in response to illness and by constitutive enzymes in neurons and/or microglia in response to psychological stress

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Figure 1: PGE2 synthesis, prostaglandin E receptor subtypes and subtype-selective compounds.
Figure 2: Proposed sites of PGE2 production during illness and psychological stress.
Figure 3: Neuronal pathways involved in stress responses to illness.
Figure 4: EP1-mediated regulation of dopaminergic systems under psychological stress.
Figure 5: Proposed mechanisms in EP2-mediated control of synaptic plasticity.

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  1. Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-konoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan

    Tomoyuki Furuyashiki & Shuh Narumiya

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Furuyashiki, T., Narumiya, S. Stress responses: the contribution of prostaglandin E2 and its receptors. Nat Rev Endocrinol 7, 163–175 (2011). https://doi.org/10.1038/nrendo.2010.194

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