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Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes., Introduction Autism spectrum disorders (ASDs) affect 1 in 68 people and are characterized by difficulties with communication, restrictive interests, and repetitive behaviors influencing the ability to function properly (1). Treatment [...]

Pregnancy maintenance in animals relies on the steroid hormone progesterone (P4), which maintains uterine inactivity by reducing uterine sensitivity to the uterotonic peptide hormone oxytocin. A new study reveals that P4's effect on uterine sensitivity to oxytocin involves a non-genomic action on the uterine oxytocin receptor, which belongs to the G-protein-coupled receptor family. This is the first evidence of a functional interaction between a G-protein linked member and a steroid.

Phospholipase C (PLC) has been shown to modulate uterine contractility during pregnancy but the mechanisms of this pathway is still unknown. In a study of the rat myometrium, formation of [3H]inositol phosphates increased two- and threefold at the quiescent midgestation phase (day 12) and at the end of gestation (day 21), respectively, in the presence of carbachol. A similar increase was in inositol 1,4,5-triphosphate was observed in the presence of AlF4-. These increases were accompanied by an increase in the level of Gq family of proteins, particularly Gqalpha and G11alpha, in the myometrium at day 12 and day 21, and a 75% decrease at midgestation.

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2 + concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2 + mobilization and extracellular Ca2 + influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation. [ABSTRACT FROM AUTHOR]

A study of subcellular distribution of G(sub q) and G(sub 11) G proteins in WRK(sub 1) cells using a selective polyclonal antibody directed towards the C-terminal decapeptide shows that these antibodies inhibit vasopressin and guanosine 5'-(alpha-thio)triphosphate susceptible phospholipase C activities thereby indicating that G(sub q) and G(sub 11) G proteins help in signal transduction. G(sub alpha-q)/ G(sub alpha-11) are correlated as indicated by immunoblot analysis.

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague-Dawley rats, as well as the respective roles of V1AR and V1BR. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective V1AR antagonist, but not a V1BR antagonist, dose-dependently prevented the rise in glycemia. V1BR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V1AR or V1BR agonists confirmed the involvement of V1AR in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l (P < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V1AR antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V1AR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes. [ABSTRACT FROM AUTHOR]