CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

Abstract

G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M 3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonistinduced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets.G protein-coupled receptors | β-cell function | mouse models | glucose homeostasis | GPCR regulation

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…Although the actual number of sites is likely fewer than 25, based on consensus sequence, these sites are predicted to be phosphorylated by several kinases, including MAPK, protein kinase G, and casein kinase 2. MAPK is a major class of kinases rapidly activated by GPCRs, including Ga q/11 -coupled receptors (53)(54)(55). Therefore, it is very likely that the activation of a given Ga q/11 -coupled receptor can trigger a signaling cascade in the cytosol, resulting in the activation of the PR (Fig.…”

Hepatic Gi signaling regulates whole-body glucose homeostasis

“…i levels were measured using FLIPR technology (Molecular Devices). Hepatocytes were exposed to increasing concentrations of CNO or AVP as described previously (51). Increases in [Ca 2+ ] i were expressed as changes in fluorescence (peak fluorescence activity minus basal fluorescence activity) divided by basal fluorescence levels.…”

Casein kinase 2 inhibition impairs spontaneous and oxytocin‐induced contractions in late pregnant mouse uterus

“…In cancer cell lines, CX‐4945 is efficacious at micromolar concentrations (Siddiqui‐Jain et al., ). Also, 10 μ m CX‐4945 is effective in enhancing insulin release in isolated pancreatic islets of mice (Rossi et al., ). These studies indicate that the potency of CX‐4945 is in the micromolar rather than the nanomolar range in isolated cells and tissue systems.…”

“…Inhibition of CK2 has been reported to increase the force and crossbridge cycling in vascular smooth muscle (Smolock, Wang, Nolt, & Moreland, 2007). It has also been associated with neurotransmitter release in the brain (Perez et al, 2011) and insulin release in pancreatic -cells (Rossi et al, 2015). Recently, the role of CK2 has been demonstrated in thrombopoiesis and platelet activation (Münzer et al, 2017).…”