Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling.
5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling.
Unité de Neurobiologie et Pharmacologie de l'INSERM, Paris, France.
C H
CH
Lammers
P
P
Schweitzer
P
P
Facchinetti
J M
JM
Arrang
S G
SG
Madamba
G R
GR
Siggins
D
D
Piomelli
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000502:physiology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000494:pharmacology*; D004790:Enzyme Induction; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D017966:Pyramidal Cells / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013004:Somatostatin / Q000037:antagonists & inhibitors / Q000502:physiology*; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D013004:Somatostatin; C548594:Alox5ap protein, rat; C060893:MK-886; D002722:Chlorobenzenes