COX‐3—a virtual pain target in humans?

Abstract

A long-sought molecule (1) was recently identified as acting independent of COX-1/-2 (2). The potent analgesic and anti-pyretic actions of acetaminophen lacking anti-inflammatory potency suggested the presence of an additional cyclo-oxygenase that could be directly responsible for acetaminophen-sensitive generation of prostanoids in neuronal systems. This could now be understood at least in part as modulation of the recently identified COX-3 (2). In canine, alternative splicing generates four different mRNA variants derived from the COX-1 geneOCOX-3, COX-1, and two partial COX-1 (denoted as PCOX-1 proteins), PCOX-1a and PCOX-1b, encoding novel members of the COX-1 protein family. Among them only canine COX-1 and canine COX-3 possessed glycosylation-dependent cyclooxygenase activity. The discovery by Dan Simmons and colleagues of COX-3 will most surely herald more interest in these pathways and enzymes as recently illustrated by the number, scholarship, and import of several commentaries (3-6).Predicted canine COX-3 is composed of COX-1 and the retained intron 1 (2). Identification of canine COX-3 might have a significant effect on understanding inflammatory messengers, characterizing new routes of prostanoid formation and pain conduction (3-6). These findings may be crucial to the development of new therapeutic agents targeting both COX-2 and COX-3 in order to reduce CNS inflammatory reactions, fever, and pain. However, this may hold true only for the dog. Database analysis of human COX-1 (Fig. 1) showed a frameshift induced by intron 1, possibly revealing COX-3 to be a virtual protein in humans. However, Western blot analysis of human aorta tissue using polyclonal antibodies directed against the first 13 amino acids of the predicted human and dog/mouse COX-3 detected (surprisingly) a 65 kDa protein postulated to be human COX-3 (2).The high sequence similarity of the canine insert to intron 1 of either human or mouse COX-1 genes and the presence of 5Ј and 3Ј consensus splice sites indicated the complete retention of intron 1 in this transcript. The predicted retention of a complete intron 1 sequence in human COX-1 (OMIM accession #176805) from a screening of several databases revealed a frameshift due to insertion of intron 1 consisting of 94 nucleotides or 98 nucleotides in the murine COX-1 gene, respectively. The frameshift after the insert (see Fig. 2) results 1) in a TGA stop codon 48 amino acids later and 2) a completely changed protein sequence not related to human COX-1. The compensating molecular events suggested by Chandrasekharan et al. are unlikely. COX-1 polymorphisms or sequencing errors concerning the nucleotides of intron 1 are implausible since recent screening of the human COX-1 gene, including the complete intron 1 region, revealed no polymorphisms or deletions in intron 1 (7). Moreover, compensation by "-1" ribosomal frame shifting has not been reported in eukaryotic mRNAs to date. COX-3 is considered a new and important lead in the generation of anti-inflammatory and analgesic agents. However,...

Cloning and Characterization of Cyclooxygenase-1b (Putative Cyclooxygenase-3) in Rat

“…C, proteins isolated from clones 2 and 3 of the COX-1b p3XFLAG-CMV-14 stably transfected COS-7 cells (see B) were subjected to Western blot analysis using anti-COX-1b polyclonal antibody. 2, clone 2; 3, clone 3. genase as in canines, because in these species the retention of the entire intron-1, which is 98 bp in rat and mouse and 94 bp in human, would shift the original reading frame of COX-1 (Dinchuk et al, 2003;Schwab et al, 2003). Hypothetically, a different initiation site or an alternative downstream splicing might restore the original COX-1 reading frame resulting in the synthesis of a peptide with homology to COX-1, except the N-terminal end, which would be encoded by the inserted intron-1.…”

Pain management in cat

“…Η COX υπάρχει σε τρεις μορφές-ισοένζυμα. Η COX-1 παρά γεται συνεχώς και είναι υπεύθυνη για τις φυσιολογικές δράσεις των προσταγλανδινών, η COX-2, αλλά και η COX-3 (κεντρική δράση) που ανακαλύφθηκε πρό σφατα, παράγονται από προσβεβλημένους ιστούς και είναι υπεύθυνες για την πρόκληση φλεγμονώδους αντί δρασης (Schwab et al 2003a(Schwab et al , 2003. Τα τελευταία χρόνια παράγονται φάρμακα με μεγαλύτερη ειδικό τητα στην αναστολή της COX-2 σε σχέση με την COX-1 (καρπροφαινη, μελοξικάμη) ή ακόμη και με δράση αποκλειστικά έναντι της COX-2 (δερακοξιμπη).…”

Downregulation of cyclooxygenase-1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats

“…The primary enzyme responsible for PG synthesis, cyclooxygenase (COX), exists in at least three isozymes. COX-1 is constitutively expressed in the gastrointestinal tract and most other tissues, whereas COX-2 is expressed at very low levels in most tissues, but has been shown to be induced at the site of inflammation; COX-3 is considered a new and important leader in the generation of anti-inflammatory and analgesic agents [15][16][17]. It is likely that COX-1 and COX-2 make different contributions to function in different cell types, and they also make different contributions to function in the same cell type under different conditions.…”