Distribution and cellular localization of insulin‐regulated aminopeptidase in the rat central nervous system

Abstract

Central infusions of angiotensin IV enhance spatial learning, memory retention and retrieval, neurotransmitter release, and long-term potentiation via interaction with a specific, high-affinity binding site. This site was recently purified and identified as the insulin-regulated aminopeptidase (IRAP). This enzyme was previously characterized as the marker protein of specialized insulin-responsive vesicles containing GLUT4 in muscle and adipose tissue. The present study provides the first comprehensive description of IRAP distribution in the adult rat brain. By using immunohistochemistry, IRAP was found to be highly expressed in selected olfactory regions, in septal and hypothalamic nuclei, throughout the hippocampal formation and cerebral cortex, and in motor and motor associated nuclei. IRAP was expressed exclusively in neurons in these regions. At the cellular level, IRAP was localized within cell bodies, excluding the nucleus, in a punctate vesicular pattern of expression. IRAP-positive immunoreactivity was also found in some proximal processes but was not detected in synaptic nerve terminals. The neurochemical composition of IRAP-containing neurons was further characterized by dual-label immunohistochemistry. IRAP was expressed in cholinergic cell bodies of the medial septum, a source of cholinergic projections to the hippocampus and cerebral cortex. The distribution of IRAP in motor and motor-associated nuclei; the colocalization of the enzyme with potential in vivo substrates, oxytocin and vasopressin in the hypothalamus; and the colocalization with GLUT4 in selected nuclei all suggest diverse physiological roles for IRAP in the rat central nervous system.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Therefore, the function of IRAP in neurons may be similar to that in insulin responsive cells . Relevant to cognitive function of IRAP/AngIV binding site in brain, the majority of IRAP was localized in intracellular vesicles in mouse brain neurons (Fernando et al, 2005. The binding of IRAP inhibitors may prolong the cell surface localization of IRAP/AngIV binding site and GLUT4 in neurons.…”

Assembling the Puzzle: Pathways of Oxytocin Signaling in the Brain

“…Brain OT is degraded by placental leucine aminopeptidase (P-LAP), an enzyme that is also cleaving AVP, met-enkephalin and leu-enkephalin, bradykinin, and somatostatin (65,66). P-LAP is widely distributed throughout the brain (67,68), including all brain regions expressing the OTRs, where it can actively control the availability of OT to its receptor and thus OTR signaling. In the hypothalamus of lactating rats, an increase in P-LAP expression was shown to play an important role in regulating the pattern of OT neuronal bursting by increasing OT availability (69).…”

Selective and Potent Agonists and Antagonists for Investigating the Role of Mouse Oxytocin Receptors

“…In the brain, the aminopeptidase oxytocinase hydrolyzes OT, AVP, enkephalins, and other neuropeptides. The enzyme is present in soluble and membrane-bound forms, and its distribution varies greatly in different brain regions (Fernando et al, 2005). In addition, binding affinity and velocity of catalysis for different substrates could also account for significant differences in local neuropeptide concentrations and final neurobiological effects.…”