Abstract
The N-acylethanolamines (NAEs), oleoylethanolamide (OEA) and palmithylethanolamide (PEA) are known to be endogenous ligands of PPARα receptors, and their presence requires the activation of a specific phospholipase D (NAPE-PLD) associated with intracellular Ca2+ fluxes. Thus, the identification of a specific population of NAPE-PLD/PPARα-containing neurons that express selective Ca2+-binding proteins (CaBPs) may provide a neuroanatomical basis to better understand the PPARα system in the brain. For this purpose, we used double-label immunofluorescence and confocal laser scanning microscopy for the characterization of the co-existence of NAPE-PLD/PPARα and the CaBPs calbindin D28k, calretinin and parvalbumin in the rat hippocampus. PPARα expression was specifically localized in the cell nucleus and, occasionally, in the cytoplasm of the principal cells (dentate granular and CA pyramidal cells) and some non-principal cells of the hippocampus. PPARα was expressed in the calbindin-containing cells of the granular cell layer of the dentate gyrus (DG) and the SP of CA1. These principal PPARα+/calbindin+ cells were closely surrounded by NAPE-PLD+ fiber varicosities. No pyramidal PPARα+/calbindin+ cells were detected in CA3. Most cells containing parvalbumin expressed both NAPE-PLD and PPARα in the principal layers of the DG and CA1/3. A small number of cells containing PPARα and calretinin was found along the hippocampus. Scattered NAPE-PLD+/calretinin+ cells were specifically detected in CA3. NAPE-PLD+ puncta surrounded the calretinin+ cells localized in the principal cells of the DG and CA1. The identification of the hippocampal subpopulations of NAPE-PLD/PPARα-containing neurons that express selective CaBPs should be considered when analyzing the role of NAEs/PPARα-signaling system in the regulation of hippocampal functions.
Highlights
N-acylethanolamines (NAEs), including oleoylethanolamide (OEA) and palmithylethanolamide (PEA), exert a variety of biological activities in the central nervous system (Calignano et al, 1998; Combs et al, 2001; Inoue et al, 2001; Rodríguez de Fonseca et al, 2001; Okamoto et al, 2007)
We performed Western blot analysis to ensure that the PPARα, N-acyl PE (NAPE)-phospholipase D (PLD), calbindin, calretinin, and parvalbumin antibodies recognized the corresponding antigens in the rat hippocampus (Figure 1A)
The biological activities of monounsaturated NAEs require both release from membrane precursors by the Ca2+-dependent NAPE-PLD and the activation of PPARα receptors that modulate Ca2+-dependent mechanisms
Summary
N-acylethanolamines (NAEs), including oleoylethanolamide (OEA) and palmithylethanolamide (PEA), exert a variety of biological activities in the central nervous system (Calignano et al, 1998; Combs et al, 2001; Inoue et al, 2001; Rodríguez de Fonseca et al, 2001; Okamoto et al, 2007). A Ca2+-activated N-acyltransferase transfers the ns-1 acyl chain of a phospholipid to the amine of phosphatidylethanolamine (PE) to generate an N-acyl PE (NAPE) (Di Marzo et al, 1994). NAPE is converted into an NAE and phosphatidic acid by phospholipase D (PLD) (Schmid, 2000). The molecular identity of the Ca2+-activated N-acyltransferase is currently unknown, while the N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) that is expressed in specific regions of the brain has been identified (Di Marzo et al, 1996; Okamoto et al, 2004). The brain tissue of NAPE-PLD knockout mice showed a five-fold reduction in the Ca2+-dependent conversion of NAPEs to NAEs, which affected both endocannabinoids, such as anandamide, and the PPARα receptor ligands PEA and OEA (Leung et al, 2006). NAPE-PLD activity is highly associated with intracellular Ca2+ stores in several types of hippocampal excitatory axon terminals (Nyilas et al, 2008)
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