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Insulin-regulated aminopeptidase or human oxytocinase (IRAP) is an enzyme commonly associated to the regulation of oxytocin levels. IRAP has a wide distribution, most notably in fat cells (adipocytes) and muscle cells (myocytes). The aminopeptidase is coexpressed with glucose transporter GLUT4 in these fat cells. The enzyme contains specific binding sites for peptides angiotensis IV (Ang IV) and LVV-hemorphin 7 (LVV-H7). These peptides are proposed to be the sites in the brain that affect memory. IRAP is found abundantly expressed with insulin in cerebral regions involved in cognitive function including the basal forebrain, amygdale, hippocampus and the entorhinal cortex.

Many studies have shown that the presence of IRAP in the brain enhances certain memory functions and the aminopeptidase poses to be a promising target for a new class of cognitive enhancing agents. While research has been done on the physiology of IRAP, the exact mechanism of action is still unknown.

Function

IRAP is a 1025 amino acid type II zinc-dependent aminopeptidase. IRAP was originally discovered as the central enzyme in hormone regulation of oxytocin. It has a wide tissue distribution but is only expressed in specific cell types. They are only found in intracellular locations . Vasopressin, oxytocin, Ang IV and LVVH7are the substrates of IRAP.

Physiological Effects

· Introduction of IRAP into fat cells releases glucose transporter GLUT4 vesicles to the plasma membrane
· Upon release, IRAP accompanies GLUT4 within specialized compartments of fat and muscle cells
· An increased level of IRAP and GLUT4 in the body's system elevates the glucose uptake of neurons
· Level of GLUT4 and IRAP in body's system is under the tight control of insulin

GLUT4's Effect on Glucose Uptake

GLUT4 is responsible for transporting glucose to responsive tissues. Insulin is secreted by the liver for glucoregulation. The hormone travels throughout the body searching for specific receptor sites of muscle, liver and brain cells. Once the insulin binds to the receptor sites, the cells become more permeable to glucose and allows the glucose uptake from the bloodstream. GLUT4 is coexpressed with IRAP and are found abundantly expressed together. They are abundantly expressed in cerebral regions involved in cognitive function such he basal forebrain, amygdale, hippocampus and the entorhinal cortex .

Effects of Peptides Ang IV and LVV-H7

IRAP contains two specific binding sites for Ang IV and LVV-H7. These two peptides are competitive inhibitors of the aminopeptidase. Ang IV has significantly less affinity to IRAP than LVVH7. Both peptides exhibit similar effects on the Central Nervous System (CNS). The presence of the peptides catalyzes potentiation in the gyrus of rats and the hippocampus region. Long-term potentiation is considered to aide memory formation and memory processing . This accelerates spatial learning capacities too. Many studies have proposed that the peptides affect memory by binding to the hippocampus, amygdala and the prefrontal cortex. At high concentrations, the peptides can activate receptors angiotensin AT1 and HFI-muopioid. These receptors greatly affect the signal transduction of main effector hormones.

The presence of zinc at the catalytic site affects the substrate-inhibitor affinity . The presence of zinc metal ions affect ANGIV and LVV-H7's binding ability by making it harder for the competitive inhibitors to bind with the aminopeptide allowing it to resume its enzymatic activity.

Effect of Vasopressin

Vasopressin is also a hormone substrate for IRAP. It has been suggested by many researchers that the effects of Ang IV and its analogs are mediated by vasopressin . While Ang IV has a rapid half-life, it still notably has a significant impact on spatial learning . The vasopressin levels in the body are controlled by insulin and subcellular distribution of IRAP. The aminopeptidase is responsible for the clearance of vasopressin from circulation. Recent studies have implicated that the inhibition of IRAP may extend the half-life of neuropeptides that modify learning and memory processes . Other physiological significances of vasopressin levels in the body's system remain to be determined.

Targeting IRAP for Cognitive Enhancement

While the research is still preliminary, studies have shown very promising results for higher efficacy of IRAP as a cognitive target than the cholinergic system. Studies have shown that this introduction of exogenous glucose administration result in the following:
• reverses of memory deficits caused by ischemia
• counteracts post-alcoholism impairments in learning and memory
• increases performance in spatial memory tasks
• enhances performance after bilateral perforant pathway lesions
• improves memory deficits caused by complications of the central cholinergic system

The current drugs approved by the Food and Drug Administration (FDA) target the cholinergic system. Most of the drugs on the market belong to the class of cholinesterase inhibitors and only demonstrate limited efficacy. In spite of limited efficacy, many drugs in development for cognitive decline still target the central cholinergic system. IRAP poses to be the next class of promising