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

Abstract

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.

• Authors: Yasuhiro Kosuge, Hiroko Miyagishi, Takashi Shinomiya, Kenta Nishiyama, Satomi Suzuki, Nobuhiro Osada, Kumiko Ishige, Migiwa Okubo, Mitsuru Kawaguchi, Yoshihisa Ito
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 38 Issue 12 Pg. 1964-8 ( 2015) ISSN: 1347-5215 [Electronic] Japan
• PMID: 26632188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• RNA, Messenger
• Receptors, Prostaglandin E, EP3 Subtype
• Dinoprostone

Topics

• Alternative Splicing
• Amyotrophic Lateral Sclerosis (genetics, metabolism)
• Animals
• Dinoprostone (metabolism)
• Disease Models, Animal
• Disease Progression
• Humans
• Male
• Mice, Transgenic
• Motor Neurons (metabolism)
• Protein Isoforms
• RNA, Messenger (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, Prostaglandin E, EP3 Subtype (genetics, metabolism)
• Signal Transduction
• Spinal Cord (metabolism)