Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation

Ribeiro, Luís F.; Catarino, Tatiana; Carvalho, Manuela; Cortes, Luísa; Santos, Sandra D.; Opazo, Patricio; Ribeiro, Lyn Rosenbrier; Oliveiros, Bárbara; Choquet, Daniel; Esteban, José A.; Peça, João; Carvalho, Ana Luı́sa

doi:10.1126/scisignal.abb1953

Cited by 22 publications

(13 citation statements)

References 71 publications

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“…We have shown that ghrelin-dependent and ghrelin-independent activities of GHSR impair native presynaptic Ca V 2.2 currents and reduce GABA release from hypothalamic and hippocampal neurons ( Cabral et al, 2014 ; Lopez Soto et al, 2015 ; Martinez Damonte et al, 2018 ). Such presynaptic effects of GHSR result in disinhibition of post-synaptic neurons and contribute to enhance GHSR mediated neuronal activation due to other molecular mechanisms, such as neuronal depolarization induced by ghrelin-mediated inhibition of voltage-gated potassium channels ( Shi et al, 2013 ) and ghrelin-dependent and ghrelin-independent increase of AMPA receptor trafficking in hippocampal neurons ( Ribeiro et al, 2014 ; Ribeiro et al, 2021 ). LEAP2 inhibition of GHSR activity converts this peptide into a putative important player in the control of neuronal plasticity and excitability.…”

Section: Discussionmentioning

confidence: 99%

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

et al. 2021

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The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.

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Section: Discussionmentioning

confidence: 99%

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

et al. 2021

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“…With the key role ghrelin has with regards to homeostatic feeding and glucose metabolism (Tschop et al, 2000 ; Gray et al, 2019 ), metabolic changes and weight less is to be expected from such a treatment. Beyond ghrelin's traditional role, a recent study showed that the intrinsic activity of GHSR-1A is important for AMPA receptor trafficking and memory formation (Ribeiro et al, 2021 ). Consequently, an inverse agonist of GHSR-1A, such as PF-5190457, may cause cognitive deficits associated with learning.…”

Section: Appetite-regulatory Peptides In Substance Use Disordermentioning

confidence: 99%

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

2021

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There is a substantial need for new pharmacological treatments of addiction, and appetite-regulatory peptides are implied as possible candidates. Appetite regulation is complex and involves anorexigenic hormones such as glucagon-like peptide-1 (GLP-1) and amylin, and orexigenic peptides like ghrelin and all are well-known for their effects on feeding behaviors. This overview will summarize more recent physiological aspects of these peptides, demonstrating that they modulate various aspects of addiction processes. Findings from preclinical, genetic, and experimental clinical studies exploring the association between appetite-regulatory peptides and the acute or chronic effects of addictive drugs will be introduced. Short or long-acting GLP-1 receptor agonists independently attenuate the acute rewarding properties of addictive drugs or reduce the chronic aspects of drugs. Genetic variation of the GLP-1 system is associated with alcohol use disorder. Also, the amylin pathway modulates the acute and chronic behavioral responses to addictive drugs. Ghrelin has been shown to activate reward-related behaviors. Moreover, ghrelin enhances, whereas pharmacological or genetic suppression of the ghrelin receptor attenuates the responses to various addictive drugs. Genetic studies and experimental clinical studies further support the associations between ghrelin and addiction processes. Further studies should explore the mechanisms modulating the ability of appetite-regulatory peptides to reduce addiction, and the effects of combination therapies or different diets on substance use are warranted. In summary, these studies provide evidence that appetite-regulatory peptides modulate reward and addiction processes, and deserve to be investigated as potential treatment target for addiction.

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“…Recently, more and more data have appeared on the so‐called ligand‐independent activity of GHS‐R1a, that is, about the active conformational state of the receptor in the absence of ligands. It is assumed that this activity is important for many physiological processes (Ribeiro et al, 2021 ).…”

Section: Ghs‐r1a In the Brainmentioning

confidence: 99%

Expression of the growth hormone secretagogue receptor 1a (GHS‐R1a) in the brain

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et al. 2021

Physiological Reports

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The review presents data on the expression of growth hormone secretagogue receptor 1a (GHS‐R1a) in the brain regions in model animals (zebrafish, rodents, primates), and in the human brain. Studies show widespread distribution of the receptor in the brain, which evidences the involvement of the receptor in many physiological processes. Using various organisms, data have been obtained regarding the participation of the GHS‐R1a in the regulation of the anti‐ and pro‐inflammatory response, proliferation, and apoptosis. It is known that the receptor plays an important role in eating behavior and is also involved in the pathogenetic mechanisms of drug addiction, obesity, and chronic alcohol consumption. Based on this, research is underway with the use of various therapeutic agents that can be used for the pharmacological correction of these conditions. This review also presents hypothetical pathways of intracellular signaling, in which GHS‐R1a may participate. A complete understanding of these mechanisms has not yet been reached. The ghrelin intracellular signaling seem to be specific to brain region and, probably, also depend on the metabolic or stress status of the organism.

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Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation

Cited by 22 publications

References 71 publications

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

An Overview of Appetite-Regulatory Peptides in Addiction Processes; From Bench to Bed Side

Expression of the growth hormone secretagogue receptor 1a (GHS‐R1a) in the brain

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