title: Cellular organization of the brain renin-angiotensin system.
abstract: A model of intracellular Ang II formation (Figure 1) implies that angiotensinogen neurons exist and that CNS Ang II acts both as a neurotransmitter as well as a neurohormone. Such a mechanism is consistent with the immunocytochemical localization of a fraction of brain Ang II in neurosecretory vesicles. To date, several dozen peptide neurotransmitters and neurohormones have been studied. Those assigned to peptidergic systems follow the generalized pathway of biosynthesis shown in Figure 1. In peptidergic systems, a prohormone and all of its processing enzymes are synthesized in the rough endoplasmic reticulum of a cell and move into the Golgi apparatus (Figure 1: #1-3). In the Golgi the prohormone and processing enzymes are packaged into the same vesicle (#3). These secretory vesicles then migrate toward the plasma membrane, frequently via axonal or dendritic projections to terminals. Within these cytoplasmic vesicles and prior to release, the processing enzymes are activated (#4) and the prohormone enzymatically processed, yielding the active peptide (#5-6). Only then do the vesicles fuse with the plasma membrane (in a calcium-dependent process), releasing their contents (#7-8). Once released, the active peptide migrates across the extracellular space and interacts with specific cell surface receptors to initiate a response (#9). Finally, receptor-bound peptide degradation is initiated by receptor-mediated endocytosis (#10-11). For angiotensin peptides to be produced intracellularly, the cell must present only one secretory pathway for Golgi packaging of renin and angiotensinogen; otherwise current theories of protein sorting would predict that these two proteins would be segregated even if synthesized within the same cell. Small quantities of co-packaged renin and angiotensinogen occurring via "spill-over" between compartments seems an unsatisfactory process for a regulated hormone system. Figure 2, depicting an extracellular mechanism for producing Ang II in the brain, has also been proposed. The mechanism of extracellular angiotensin formation is consistent with the molecular information encoded within the component proteins, known mechanisms of protein secretio, well-defined systemic renin-angiotensin enzymatic cascades, and demonstration of all the components of the renin-angiotensin system in the extracellular compartments of the brain. This model (Figure 2) allows independently coordinated gene expression and synthesis of renin (#1R), angiotensinogen (#1A), and angiotensin-converting enzyme (# 1C) in the same or different cells.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Research Institute, Cleveland Clinic Foundation, Ohio 44106.
authors.forename: R B
authors.initials: RB
authors.lastname: Moffett
authors.forename: F M
authors.initials: FM
authors.lastname: Bumpus
authors.forename: A
authors.initials: A
authors.lastname: Husain
mesh_terms: D000803:Angiotensin I / Q000235:genetics / Q000502:physiology; D000804:Angiotensin II / Q000235:genetics / Q000502:physiology; D000808:Angiotensinogen / Q000235:genetics / Q000502:physiology; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000502:physiology; D007150:Immunohistochemistry; D008954:Models, Biological; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology; D012083:Renin / Q000235:genetics / Q000502:physiology; D012084:Renin-Angiotensin System
chemical_list: D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin