Abstract
Placental leucine aminopeptidase/insulin-regulated aminopeptidase (P-LAP/IRAP) regulates vasopressin and oxytocin levels in the brain and peripheral tissues by controlled degradation of these peptides. In this study, we determined the relationship between P-LAP/IRAP and vasopressin levels in subregions of the murine brain. P-LAP/IRAP expression was observed in almost all brain regions. The expression patterns of P-LAP/IRAP and vasopressin indicated that cells expressing one of these protein/peptide were distinct from those expressing the other, although there was significant overlap between the expression regions. In addition, we found reciprocal diurnal rhythm patterns in P-LAP/IRAP and arginine vasopressin (AVP) expression in the hippocampus and pituitary gland. Further, synchronously cultured PC12 cells on treatment with nerve growth factor (NGF) showed circadian expression patterns of P-LAP/IRAP and enzymatic activity during 24 h of incubation. Considering that vasopressin is one of the most efficient peptide substrates of P-LAP/IRAP, these results suggest a possible feedback loop between P-LAP/IRAP and vasopressin expression, that regulates the function of these substrate peptides of the enzyme via translocation of P-LAP/IRAP from intracellular vesicles to the plasma membrane in brain cells. These findings provide novel insights into the functions of P-LAP/IRAP in the brain and suggest the involvement of these peptides in modulation of brain AVP functions in hyperosmolality, memory, learning, and circadian rhythm.
Highlights
Placental leucine aminopeptidase (P-LAP) was first purified from retroplacental serum as a soluble protein (Tsujimoto et al, 1992)
These results indicate that P-LAP/insulinregulated membrane aminopeptidase (IRAP) plays important roles in the modulation of several brain functions
We identified reciprocal rhythmic increases and decreases in P-LAP/IRAP and arginine vasopressin (AVP) levels in several regions of the brain
Summary
Placental leucine aminopeptidase (P-LAP) was first purified from retroplacental serum as a soluble protein (Tsujimoto et al, 1992). Placental leucine aminopeptidase/insulin-regulated aminopeptidase (P-LAP/IRAP) is a multifunctional enzyme that plays several pathophysiological roles. Similar to the case of GLUT4-containing vesicles, P-LAP/IRAP is involved in vesicular trafficking of the somatostatin type 2A receptor to the plasma membrane in hippocampal neurons and exerts an inhibitory effect on seizure activity (De Bundel et al, 2015). Inhibition of P-LAP/IRAP activity in the hypothalamus leads to increased frequency of milk ejection reflexes due to enhancement in oxytocin concentration These results indicate that P-LAP/IRAP plays important roles in the modulation of several brain functions. This enzyme is an important player in host defense systems, such as antigen cross-presentation, and Toll-like receptor 9 signaling (Saveanu et al, 2009; Babdor et al, 2017). The functional significance of the present results is discussed in the context of vasopressin being one of the most efficient peptide substrates of P-LAP/IRAP (Tsujimoto et al, 1992; Matsumoto et al, 2000)
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