title: Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice.
abstract: Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitary-adrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wild-type or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P<0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P <0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline- and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P <0.05, 268.9% P <0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. hiroim@ninds.nih.gov
authors.forename: M
authors.initials: M
authors.lastname: Yoshida-Hiroi
authors.forename: M J
authors.initials: MJ
authors.lastname: Bradbury
authors.forename: G
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: N
authors.initials: N
authors.lastname: Hiroi
authors.forename: W W
authors.initials: WW
authors.lastname: Vale
authors.forename: G E
authors.initials: GE
authors.lastname: Novotny
authors.forename: H G
authors.initials: HG
authors.lastname: Hartwig
authors.forename: W A
authors.initials: WA
authors.lastname: Scherbaum
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
mesh_terms: D000311:Adrenal Glands / Q000201:enzymology / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019439:Chromaffin Cells / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D002864:Chromogranins / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D004745:Enkephalins / Q000235:genetics; D004837:Epinephrine / Q000096:biosynthesis / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009478:Neuropeptide Y / Q000235:genetics; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013312:Stress, Physiological / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D002864:Chromogranins; D004745:Enkephalins; D009478:Neuropeptide Y; D010750:Phosphoproteins; D011498:Protein Precursors; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; C029992:proenkephalin; D000098682:Steroidogenic Acute Regulatory Protein; D000324:Adrenocorticotropic Hormone; D010625:Phenylethanolamine N-Methyltransferase; D003345:Corticosterone; D004837:Epinephrine