Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region

Vasilache, Ana Maria; Andersson, Josefin; Nilsberth, Camilla

doi:10.1016/j.neulet.2007.06.048

Cited by 25 publications

(20 citation statements)

References 13 publications

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“…In the mouse preoptic region of the anterior hypothalamus, the expression profile of EP3 variants was reportedly not changed by immune challenge induced by systemic injection of lipopolysaccharide. 22) Taken together, these findings suggest that EP3 receptor splicing is not activity-dependent in the spinal cord or the hypothalamus.…”

Section: Resultsmentioning

confidence: 84%

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Kosuge

Miyagishi

Shinomiya

et al. 2015

Biological & Pharmaceutical Bulletin

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Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with adult onset, characterized by progressive loss of motor neurons. Prostaglandin E2 (PGE2), a lipid mediator, exerts its biological functions by binding to four subtypes of E-prostanoid (EP1-4). Among them, EP3 has been shown to have multiple isoforms, EP3α, EP3β, and EP3γ, produced by alternative splicing. Since PGE2 has been shown to have important pathophysiological roles in ALS, experiments were performed to identify EP3 receptor isoform(s) in spinal motor neurons of wild-type (WT) and ALS model (G93A) mice. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of adult mice demonstrated expression of EP3α and EP3γ mRNAs in the lumbar spinal cord, whereas EP3β mRNA was barely detectable. Laser capture microdissection was used to dissect out motor neurons from frozen samples of lumbar spinal cord in these mice for analysis by real-time PCR. We found that expression of EP3γ mRNA was predominant in these neurons, whereas EP3α and EP3β mRNAs were undetectable. At the early symptomatic stage, the mRNA expression profiles of these splice isoforms in G93A motor neurons were comparable to those in neurons from WT mice. These results suggest that the PGE2-to-EP3 signaling pathway is mediated mainly by the EP3γ isoform in the motor neurons of mice, and that modulation of the EP3γ isoform in motor neurons may be a promising new therapeutic approach for ALS.Key words motor neuron; prostaglandin E2 (PGE2); E-prostanoid 3 (EP3) receptor isoform; amyotrophic lateral sclerosis; laser microdissection Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by selective loss of motor neurons in the cortex and spinal cord. ALS causes progressive muscular paralysis reflecting the degeneration of motor neurons, a poor quality of life, and eventual death within 3-5 years of diagnosis. 1) Although multiple processes are thought to be implicated in the pathogenesis of ALS, including oxidative stress, mitochondrial dysfunction, excitotoxicity, RNA-processing errors and abnormal protein aggregation, 2) the mechanism underlying the selective death of motor neurons has not yet been clarified. Recently, inflammation in the spinal cord has been highlighted as an important pathogenic mechanism in ALS, and levels of prostaglandin E2 (PGE2), a key proinflammatory mediator, are increased in postmortem brain tissue, cerebrospinal fluid and serum from patients with sporadic ALS.3,4) It has also been shown that ALS model mice have markedly increased levels of PGE2 in both the cerebral cortex and spinal cord. 5) Moreover, the expression of cyclooxygenase (COX)-2, which plays a key role in the synthesis of prostaglandins from arachidonic acid, is up-regulated in the spinal cord of ALS patients and model mice.6,7) Treatment with celecoxib, a selective COX-2 inhibitor, delays the onset of the disease and prolongs survival.8) Recently, we have also shown that the level of microsomal PGE synthase-1 (mPGES-1), catalyzing the ter...

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Section: Resultsmentioning

confidence: 84%

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Kosuge

Miyagishi

Shinomiya

et al. 2015

Biological & Pharmaceutical Bulletin

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“…We found that c-fos mRNA expression in the hypothalamus, as demonstrated by real-time RT-PCR, was not only maintained, but augmented, in the mPGES-1 knock-out mice, corroborating our qualitative observation that Fos protein expression tended to be stronger in the PVH and other autonomic relay nuclei in mPGES-1 knock-out mice than in wild-type mice. Although these tentative observations will require additional quantitative studies, an attenuated Fos expression by a direct central action of PGE 2 , although contradictory to the fact that PGE 2 injected centrally induces Fos (Lacroix et al, 1996), would be consistent with the predominant EP 3 receptor expression in many brainstem autonomic relay nuclei (Ek et al, 2000;Engblom et al, 2001), because the most abundant isoform of the EP 3 receptor is coupled to inhibitory G-proteins that reduce cAMP levels (Irie et al, 1993;Vasilache et al, 2007). Therefore, as suggested by Zhang et al (2003), if anything, PGE 2 binding to the EP 3 receptor may be expected to result in inhibition of these neurons [as is hypothesized for thermosensory preoptic neurons (Lazarus et al, 2007)] and hence reduced Fos expression, as indicated by the present results.…”

Section: Discussionmentioning

confidence: 99%

Inducible Prostaglandin E₂Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge

Elander¹,

Engström²,

Ruud³

et al. 2009

J. Neurosci.

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Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E 2 -synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which (1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and (2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE 2 synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

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“…The mRNA expressions of EP3 receptor are most abundant in the olfactory system, hippocampus, and subcortical telencephalic structures in the septal region and amygdala of the brain (Sugimoto et al, 1994; Ek et al, 2000; Nakamura et al, 2000). EP3 receptor mRNA are expressed mostly in subcortical-hypothalamic regions of the brain owing to their role in thermoregulation (Vasilache et al, 2007). The EP3 receptor has multiple splice variants differing in their C-terminal tails.…”

Section: Role Of Prostaglandin Receptors In Ichmentioning

confidence: 99%

Putative Role of Prostaglandin Receptor in Intracerebral Hemorrhage

Mohan¹,

Ahmad²,

Glushakov³

et al. 2012

Front. Neur.

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Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH) strokes, and 3% are subarachnoid hemorrhage strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37–38% of patients between the ages of 45 and 64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptors cross-reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic-adenosine monophosphate and calcium (Ca2+) signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and brain injuries alike.

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Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region

Cited by 25 publications

References 13 publications

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Inducible Prostaglandin E₂Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge

Putative Role of Prostaglandin Receptor in Intracerebral Hemorrhage

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Expression of PGE2 EP3 receptor subtypes in the mouse preoptic region

Cited by 25 publications

References 13 publications

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

Inducible Prostaglandin E2Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge

Putative Role of Prostaglandin Receptor in Intracerebral Hemorrhage

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Inducible Prostaglandin E₂Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge