Translating biased signaling in the ghrelin receptor system into differential in vivo functions

Abstract

Biased signaling has been suggested as a means of selectively modulating a limited fraction of the signaling pathways for G-protein–coupled receptor family members. Hence, biased ligands may allow modulation of only the desired physiological functions and not elicit undesired effects associated with pharmacological treatments. The ghrelin receptor is a highly sought antiobesity target, since the gut hormone ghrelin in humans has been shown to increase both food intake and fat accumulation. However, it also modulates mood, behavior, growth hormone secretion, and gastric motility. Thus, blocking all pathways of this receptor may give rise to potential side effects. In the present study, we describe a highly promiscuous signaling capacity for the ghrelin receptor. We tested selected ligands for their ability to regulate the various pathways engaged by the receptor. Among those, a biased ligand, YIL781, was found to activate the Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-arrestin or other G-protein coupling is sufficient to decrease food intake.

Conformational plasticity of the intracellular cavity of GPCR−G-protein complexes leads to G-protein promiscuity and selectivity

“…Upon binding agonists, GPCRs couple to single or multiple Gprotein subtypes and initiate cell-specific signaling pathways. Studies with novel bioluminescence resonance energy transfer sensors show GPCRs exhibit a promiscuous and "pluridimensional" behavior, coupling to many Gα-proteins with different strengths (1)(2)(3)(4). While a receptor may show similar affinity to different Gα proteins, the cellular context may render certain couplings moot (1,(5)(6)(7)(8)(9).…”

Serum Ghrelin Levels in Saudi Obese Asthmatic School-Children—Correlation with Interleukin-4, Interleukin-5, and Interleukin-21

“…Significant higher plasma levels of ghrelin and visfatin in asthmatic patients may imply that ghrelin exerts an anti-inflammatory effect in asthma, suggesting that it might be a new anti-inflammatory drug for asthmatic patients [16]. However, targeting the ghrelin receptor may induce unacceptable adverse effects and thus may have limited clinical use [17]. Nonetheless, in another report, there was a strong negative correlation between plasma ghrelin and serum IgE levels, in which ghrelin suppressed IgE production [18].…”

Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model

“…This phenomenon is referred to as biased signaling, and implies that a restricted number of signaling pathways are employed instead of the full subset, depending on the ligand that binds the receptor [27]. One of these biased agonists recently described for the ghrelin-R is YIL781 [28]. Primarily, this compound was classified as a ghrelin-R antagonist, but recently it was unveiled that this ligand preferentially activates Gα q/11 and Gα 12 and behaves antagonistic or modestly inverse agonistic toward the other pathways [28].…”

“…One of these biased agonists recently described for the ghrelin-R is YIL781 [28]. Primarily, this compound was classified as a ghrelin-R antagonist, but recently it was unveiled that this ligand preferentially activates Gα q/11 and Gα 12 and behaves antagonistic or modestly inverse agonistic toward the other pathways [28]. YIL781 does not lead to β-arrestin recruitment and hence does not induce a rapid termination of Gα q/11 signaling (Table 1).…”