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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Intracellular-specific colocalization of prostaglandin E₂ synthases and cyclooxygenases in the brain

¹Departments of Pediatrics and Ophthalmology and Pharmacology, Research Center of Hôpital Sainte-Justine, Montréal H3T 1C5; ²Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Kirkland H9R 4P8; ³Department of Pharmacology and Therapeutics, McGill University, Montréal H3G 1Y6; and ⁴Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4; and ⁵Department of Pediatrics, University of California, San Francisco, California 94143-0544

Submitted 3 February 2004 ; accepted in final form 30 June 2004

Prostaglandin E₂ (PGE₂) is the major primary prostaglandin generated by brain cells. However, the coordination and intracellular localization of the cyclooxygenases (COXs) and prostaglandin E synthases (PGESs) that convert arachidonic acid to PGE₂ in brain tissue are not known. We aimed to determine whether microsomal and cytosolic PGES (mPGES-1 and cPGES) colocalize and coordinate activity with either COX-1 or COX-2 in brain tissue, particularly during development. Importantly, we found that cytosolic PGES also associates with microsomes (cPGES-m) from the cerebrum and cerebral vasculature of the pig and rat as well as microsomes from various cell lines; this seemed dependent on the carboxyl terminal 35-amino acid domain and a cysteine residue (C58) of cPGES. In microsomal membranes from the postnatal brain and cerebral microvessels of mature animals, cPGES-m colocalized with both COX-1 and COX-2, whereas mPGES-1 was undetectable in these microsomes. Accordingly, in this cell compartment, cPGES could coordinate its activity with COX-2 and COX-1 (partly inhibited by NS398); albeit in microsomes of the brain microvasculature from newborns, mPGES-1 was also present. In contrast, in nuclei of brain parenchymal and endothelial cells, mPGES-1 and cPGES colocalized exclusively with COX-2 (determined by immunoblotting and immunohistochemistry); these PGESs contributed to conversion of PGH₂ into PGE₂. Hence, contrary to a previously proposed model of exclusive COX-2/mPGES-1 coordination, COX-2 can coordinate with mPGES-1 and/or cPGES in the brain, depending on the cell compartment and the age group.

cytosolic prostaglandin E synthase; MPGES-1; MPGES-2; hippocampus; membrane association

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