ß3 adrenergic receptor activation modulates connexin 43 activity to relax human myometrium.

Preterm labor, delivery prior to 37 completed weeks of gestation, is the leading cause of infant morbidity and mortality. ß3 adrenergic receptor protein expression is increased in the myometrium during pregnancy, and the agonist, mirabegron, relaxes the myometrium making the ß3 adrenergic receptor a potential therapeutic target in PTL. ß3 adrenergic receptor has been shown to activate the tyrosine kinase, Src, which can down regulate connexin 43, a contractile associated protein which promotes the formation of gap junctions that create an electrical syncytium. We hypothesize that mirabegron downregulates connexin 43, imparting quiescence effects on the myometrium. Employing contractile studies, we demonstrate that Src is involved in the mirabegron-induced relaxation of contracting pregnant human myometrial tissue strips. Western blot analysis demonstrates that Src kinase expression is decreased in both preterm and term laboring myometrial tissue. Imaging revealed that mirabegron stimulation of the ß3 adrenergic receptor phosphorylates tyrosine at position Y265 on connexin 43 in pregnant human uterine myocytes. Western blot analysis and immunofluorescent imaging indicate that mirabegron decreases the expression of connexin 43 and mediates relaxation over a 24-h exposure period, suggesting that mirabegron has long lasting quiescent effects on the human myometrium. The relationship between the ß3 adrenergic receptor and down regulation of the contractile associated protein connexin 43 through activation of Src kinase suggests that mirabegron may be useful in combination tocolysis.

Maturity-Onset Diabetes of the Young: Mutations, Physiological Consequences, and Treatment Options.

Maturity-Onset Diabetes of the Young (MODY) is a rare form of diabetes which affects between 1% and 5% of diagnosed diabetes cases. Clinical characterizations of MODY include onset of diabetes at an early age (before the age of 30), autosomal dominant inheritance pattern, impaired glucose-induced secretion of insulin, and hyperglycemia. Presently, 14 MODY subtypes have been identified. Within these subtypes are several mutations which contribute to the different MODY phenotypes. Despite the identification of these 14 subtypes, MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus due to an overlap in clinical features, high cost and limited availability of genetic testing, and unfamiliarity with MODY outside of the medical profession. The primary aim of this review is to investigate the genetic characterization of the MODY subtypes. Additionally, this review will elucidate the link between the genetics, function, and clinical manifestations of MODY in each of the 14 subtypes. In providing this knowledge, we hope to assist in the accurate diagnosis of MODY patients and, subsequently, in ensuring they receive appropriate treatment.