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

Abstract

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 GHSR1a 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. GPCR oligomers | glucose homeostasis

Ghrelin

“…The differential effects of ghrelin on insulin secretion appear to be correlated with ghrelin and/or glycemic conditions (23). A recent study suggests that ghrelin's effect on insulin secretion depends on the heteromerization between GHS-R and the somatostatin receptor 5, both of which are G-protein-coupled receptors (GPCRs) (24). The heteromerization varies according to the ratio of somatostatin:ghrelin in the serum; this ratio determines whether the Gα(i/o) subunit or the Gα(q) subunit is being activated, which leads to activation of different signal transduction pathways that result in different insulin responses to ghrelin (24).…”

MECHANISMS IN ENDOCRINOLOGY: Regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions

“…The different fasting durations used in these studies may account for the differences in results. Fasting increases circulating ghrelin levels (47,48) and it has been recently demonstrated that the (ghrelin):(SST) ratio determines whether ghrelin will be stimulatory or inhibitory on insulin secretion (33). Under fasting conditions, a high (ghrelin):(SST) ratio promotes GHSR:SST5 heteromer formation and GHSR then couples to Ga i/o to inhibit insulin secretion.…”

Modulation of pancreatic exocrine and endocrine secretion

“…Ghrelin also regulated the effect of somatostatin on GSIS. Under conditions of low glucose, ghrelin was elevated concomitant with a reduction in somatostatin [10**]. The ghrelin receptor (growth hormone secretagogue receptor type 1a (GHS-R1a)) dimerized with somatostatin receptor, subtype 5 (SSTR5) located on β-cells.…”