Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release

Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)–G-protein coupling to Gα_i/o instead of Gα_q11 and dependence on energy balance. Here we present evidence for an equilibrium model of receptor heteromerization that fulfills these criteria. We show that GHS-R1a coupling to Gα_i/o rather than Gα_q11 requires interactions between GHS-R1a and SST receptor subtype 5 (SST5) and that in the absence of SST5 ghrelin enhances GSIS. At concentrations of GHS-R1a and SST5 expressed in islets, time-resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, suppresses GSIS and cAMP accumulation. GHS-R1a–G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghrelin to SST. A high ratio enhances heteromer formation and Gα_i/o coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a–Gα_q11 coupling. The [ghrelin]/[SST] ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet SST concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than SST establishes inhibitory tone on the β-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential regulation of islet function by ghrelin and SST. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context.     

Curcumin Modulates α-Synuclein Aggregation and Toxicity

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Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases

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Investigation of the topical application of procyanidin oligomers from apples to identify their potential use as a hair-growing agent

Background Procyanidins are a family of condensed tannins, which have been shown to possess hair‐growing activity in both the in vitro and in vivo murine models. Aims We report a 12‐month clinical study aimed at treating male pattern baldness by external application of 0.7% apple procyanidin oligomers. Patients/methods A double‐blind clinical test involving a total of 43 subjects was performed. Twenty‐one men in the procyanidin group and 22 men in the placebo control group were subjected to analysis. In the first 6 months, we compared the procyanidin and the placebo groups to assess the medicinal effects of procyanidin oligomers. The application time of the procyanidin group was subsequently extended to 12 months, and the time course of its remedial value was examined. Results The increase in total number of hairs in a designated scalp area of the procyanidin group subjects after the 6‐month trial was significantly greater than that of the placebo control group subjects (procyanidin, 3.3 ± 13.0 (mean ± SD)/0.50 cm²; placebo, ?3.6 ± 8.1/0.50 cm²; P < 0.001, two‐sample t‐test). Time course‐dependent improvement in hair density was observed in the procyanidin subjects. No adverse side effects were observed in any of the subjects. Procyanidin therapy thus shows potential hair‐growing activity.