The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions
Akito Tanoue, … , Toyoki Mori, Gozoh Tsujimoto
Akito Tanoue, … , Toyoki Mori, Gozoh Tsujimoto
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):302-309. https://doi.org/10.1172/JCI19656.
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Article Endocrinology

The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions

Abstract

The neurohypophyseal peptide [Arg8]-vasopressin (AVP) exerts major physiological actions through three distinct receptor isoforms designated V1a, V1b, and V2. Among these three subtypes, the vasopressin V1b receptor is specifically expressed in pituitary corticotrophs and mediates the stimulatory effect of vasopressin on ACTH release. To investigate the functional roles of V1b receptor subtypes in vivo, gene targeting was used to create a mouse model lacking the V1b receptor gene (V1bR–/–). Under resting conditions, circulating concentrations of ACTH and corticosterone were lower in V1bR–/– mice compared with WT mice (V1bR+/+). The normal increase in circulating ACTH levels in response to exogenous administration of AVP was impaired in V1bR–/– mice, while corticotropin-releasing hormone–stimulated ACTH release in the V1bR–/– mice was not significantly different from that in the V1bR+/+ mice. AVP-induced ACTH release from primary cultured pituitary cells in V1bR–/– mice was also blunted. Furthermore, the increase in ACTH after a forced swim stress was significantly suppressed in V1bR–/– mice. Our results clearly demonstrate that the V1b receptor plays a crucial role in regulating hypothalamic-pituitary-adrenal axis activity. It does this by maintaining ACTH and corticosterone levels, not only under stress but also under basal conditions.

Authors

Akito Tanoue, Shuji Ito, Kenji Honda, Sayuri Oshikawa, Yoko Kitagawa, Taka-aki Koshimizu, Toyoki Mori, Gozoh Tsujimoto

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Figure 1

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Generation of V1b receptor–deficient mice. (a) Simplified restriction ma...
Generation of V1b receptor–deficient mice. (a) Simplified restriction map of the V1b receptor gene and structure of the targeting vector. The coding region of the exon is boxed. Neo, neo cassette; DT-A, diphtheria toxin A fragment gene; B, BamHI; E, EcoRI; EV, EcoRV; H, HindIII; S, SacI; Sp, SpeI; X, XhoI. (b) Southern blot analysis of tail DNA. DNA was digested with EcoRV and the blot was hybridized with the 5′ probe shown in a. The 14.0-kb band is derived from the WT allele (Wild) and the 2.8-kb band from the targeted allele (Mutant). (c) RT-PCR analysis of the RNA from tissues of V1bR+/+ and V1bR –/– mice. Ethidium bromide stainings of RT-PCR fragments are shown at left. The V1b receptor mRNA transcripts were detected and are shown as 540-bp fragments. The control for RT-PCR analysis was provided by detection of the 662-bp fragment of the GAPDH message. Southern blots of the RT-PCR fragments are shown at right. The specificities of the amplified fragments were assessed using 32P-labeled probes specific for each receptor subtype. Lane 1, brain; lane 2, hippocampus; lane 3, pituitary; lane 4, heart; lane 5, lung; lane 6, liver; lane 7, kidney; lane 8, spleen; lane 9, aorta.