Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia

Abstract

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.

Building GLUT4 Vesicles: CHC22 Clathrin’s Human Touch

“…Hence, correct sorting and packaging of GLUT4 into the GSC/IRVs is relevant beyond peripheral tissues [63][64][65][66]. IRAP is expressed in specific brain regions, including the hippocampus, neocortex, and motor neurons [63,67,68], sortillin is involved in chaperoning neuronal receptors [69] and a GSC-like compartment regulates somatostatin receptor storage in pituitary cells [70].…”

Editorial: Physiological, Pathological Roles and Pharmacology of Insulin Regulated Aminopeptidase

“…IRAP belongs to the M1 family of aminopeptidases (EC 3.4.11.3) and is also known as cystinyl aminopeptidase, placental leucine aminopeptidase (PLAP), and oxytocinase. The reported biological functions of IRAP include: (i) the regulation of trafficking of glucose transporter 4 (Keller, 2003), (ii) the generation of antigenic peptides for cross-presentation (Saveanu et al, 2009), (iii) T-cell receptor signaling (Evnouchidou et al, 2020), (iv) the regulation of placental oxytocin levels (Tsujimoto et al, 1992), (v) not well-understood roles in cognition and other central nervous system functions possibly through the regulation of oxytocin and vasopressin levels in the brain (Herbst et al, 1997;Albiston et al, 2011;Bernstein et al, 2017) or altered glucose uptake (Fernando et al, 2008;Albiston et al, 2011;Ismail et al, 2017), and (vi) the regulation of organ fibrosis (T. Gaspari, personal communication). All these roles have been associated with at least one of the two functional components of IRAP: an extracellular C-terminal domain that contains the M1 exopeptidase catalytic site and a 110 amino-acid long cytosolic N-terminal domain, connected by a single transmembrane-spanning region.…”

Perspectives of Pitocin administration on behavioral outcomes in the pediatric population: recent insights and future implications

“…It is during this time of Pitocin administration that fetuses are indirectly exposed to~6 mL of synthetic oxytocin per hr (assuming 20 U Pitocin in 1000 cc D5LR). The half-life of Pitocin is relatively short (~10-12 min) and in the periphery, Pitocin is most likely metabolized by the same enzyme that inactivates endogenous oxytocin: placental leucine aminopeptidase, a membrane-bound enzyme also expressed in magnocellular neurons of the anterior hypothalamus (Tobin et al, 2014;Bernstein et al, 2017). Against this background, much of what we know about the studied subject is based on rodents, as these animals afford a higher degree of experimental manipulation and observation than humans (Kenkel et al, 2014).…”