AVPR1B

AVPR1B (V1bR) is a vasopressin-responsive G protein-coupled receptor that couples AVP signaling to neuroendocrine, behavioral, and metabolic outputs (PMID:20846299, PMID:39217353). On anterior pituitary corticotrophs it mediates AVP-stimulated ACTH release during acute stress, since genetic knockout and selective pharmacological antagonism both blunt stress-induced ACTH and corticosterone responses (PMID:20846299), an effect confirmed across additional stress paradigms and species by antagonist blockade (PMID:23580725). In Cushing's disease corticotropinomas, AVPR1B is dramatically overexpressed and drives desmopressin-induced ACTH hypersecretion and proliferative/Ca2+ responses that are abolished by an AVPR1B-selective antagonist, with receptor levels correlating with plasma ACTH (PMID:23884782); this overexpression is driven by USP8 mutations that upregulate AVPR1B promoter activity (PMID:35451730). Beyond the HPA axis, AVPR1B is expressed exclusively in pancreatic α cells, where AVP-stimulated glucagon secretion promotes glucose-dependent insulin release from β cells via paracrine GLP-1R signaling (PMID:39217353), and in the dorsal hippocampus it modulates anxiety-related behavior in a subregion-specific manner (PMID:18508119).

1. 2008 Medium

   Established that AVPR1B has a central behavioral role beyond endocrine signaling, anatomically localized to the dorsal hippocampus.

   Evidence Site-specific microinfusion of selective Avpr1b antagonist into dorsal vs. ventral hippocampus with elevated plus-maze and shock-probe behavioral tests in rats

   PMID:18508119

   Open questions at the time

   • Single lab pharmacological study
   • Downstream circuit and signaling mechanism in hippocampus not defined
   • Endogenous AVP source driving the response not identified
2. 2010 High

   Demonstrated by genetic and pharmacological convergence that pituitary Avpr1b is required for AVP-driven ACTH release during acute stress, defining its core HPA-axis function.

   Evidence Avpr1b knockout mice and selective antagonist treatment with plasma ACTH/corticosterone measurement after restraint and swim stress

   PMID:20846299

   Open questions at the time

   • Sex-dependent corticosterone effect not mechanistically explained
   • Intracellular signaling coupling not resolved
3. 2013 High

   Identified AVPR1B as the receptor underlying aberrant desmopressin-induced ACTH secretion specifically in corticotropinomas, linking receptor overexpression to disease.

   Evidence Primary cultures of human corticotropinomas and other adenomas with desmopressin ± selective antagonist; Ca2+ imaging, ACTH secretion/expression, qRT-PCR

   PMID:23884782

   Open questions at the time

   • Cause of receptor overexpression not yet established at this stage
   • Link between Ca2+ signaling and proliferation not detailed
4. 2013 Medium

   Confirmed across species and stress modality that V1bR antagonism blunts ACTH, reinforcing AVP's positive regulation of pituitary ACTH.

   Evidence Rat heat-stress model with Nelivaptan; plasma ACTH/corticosterone and intrapituitary V1bR/ACTH by western blot

   PMID:23580725

   Open questions at the time

   • Single lab
   • Regulation of intrapituitary V1bR levels by circulating AVP not mechanistically dissected
5. 2022 Medium

   Connected AVPR1B overexpression in Cushing's disease to a transcriptional driver, showing USP8 mutations upregulate the AVPR1B promoter.

   Evidence qRT-PCR/IHC of AVP receptors in 47 Cushing's disease tumors plus dual-luciferase AVPR1B promoter assay with mutant vs. wild-type USP8

   PMID:35451730

   Open questions at the time

   • Mechanism by which mutant USP8 activates the promoter not defined
   • Single lab
   • Selectivity of effect on AVPR1B vs. AVPR2 not fully resolved
6. 2024 Medium

   Extended AVPR1B function to metabolic regulation, defining an α-cell-restricted receptor that orchestrates paracrine α-to-β cell crosstalk.

   Evidence Single-cell transcriptomics of islet V1bR expression; AVP stimulation of whole islets vs. purified β cells with V1bR, GLP-1R, and GCGR antagonists; glucagon/insulin secretion assays

   PMID:39217353

   Open questions at the time

   • Single lab
   • In vivo physiological relevance of the islet circuit not established
   • Intracellular signaling from V1bR to glucagon release not detailed

• The intracellular G protein coupling and downstream signaling cascade of AVPR1B remains uncharacterized in the available corpus across its endocrine, behavioral, and metabolic contexts.
• No structural model of receptor-ligand engagement
• G protein/second messenger coupling not resolved beyond Ca2+ observations
• Unifying mechanism across tissues not established