Chronic activation of a designer Gq-coupled receptor improves β cell function

Abstract

Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell G q signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated G q leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer G q -coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of G q -type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

“…DREAMM revealed an intense increase in FDG uptake in the DRN (Supplementary Figure S10)-supporting our prior observations (Alexander et al, 2009;Krashes et al, 2011) and that of others (Jain et al, 2013;Carter et al, 2014) that hM3Dq displays robust and continuous activity even with long-term stimulation by CNO-also confirming our ex vivo slice results.…”

“…Thus, to better mimic the long-term effects of antidepressants, we decided to take advantage of our chemogenetic system to chronically and non-invasively modulate neuronal activity over a long period of time and then investigate the effects of chronically activating DRN serotonergic neurons on the behaviors of animals. As previously described (Jain et al, 2013), CNO (5 mg/kg/day) was administered continuously via drinking water for 3 weeks (Figure 3a). Then the electrophysiological properties of DRN serotonergic neurons were assessed to determine whether these neurons can still be activated by CNO after long-term CNO stimulation.…”

Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

“…To overcome this obstacle, we took advantage of DREADD technology and generated Gfap-hM3Dq transgenic mice (16).The engineered GPCR approach has been used by others to identify novel signaling pathways that play critical physiological roles in vivo (52)(53)(54). For example, Jain et al used hM3Dq transgenic mice to demonstrate that Gq-GPCR signaling in pancreatic β cells led to activation of ERK1/2 and IRS2 signaling; this activation led to markedly improved β cell function (55). Recent studies where Gfap-hM3Dq was used to activate enteric glia revealed novel mechanisms of glial regulation of gastrointestinal functions (15,56).…”

Muscarinic Control of MIN6 Pancreatic β Cells Is Enhanced by Impaired Amino Acid Signaling

“…nutrient stress. Beneficial effects of M3R activation in ␤ cells have been deduced from defects in M3R knockout mice and were also revealed in studies of a designer G q -coupled receptor engineered by incorporating mutations in M3R that rendered the receptor unresponsive to ACh but selectively sensitive to activation by the pharmacologically inert compound clozapine-N-oxide (13,(31)(32)(33). Chronic activation of the ␤ cell G q -coupled designer receptor in mice resulted in enhanced insulin release, decreased blood glucose concentrations, augmented ␤ cell mass because of stimulation of ␤ cell proliferation, increased insulin content, and amplified expression of several genes critical for ␤ cell function (13,33).…”

“…Signaling by the M3R also activates ERK1/2 in ␤ cells, most likely downstream of elevated intracellular calcium (12)(13)(14). ERK1/2 activation enhances insulin gene transcription following nutrient-induced insulin secretion (15)(16)(17)(18).…”