Ghrelin upregulates the phosphorylation of the GluN2B subunit of the NMDA receptor by activating GHSR1a and Fyn in the rat hippocampus

Abstract

Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity. However, it depended on the activation of GHSR1a and Fyn as it was blocked by D-Lys3-GHRP-6 and PP2, respectively. Inhibitors for G-protein-regulated second messengers, such as Rp-cAMP, H89, TBB, ryanodine, and thapsigargin, unexpectedly enhanced GluN2B phosphorylation, suggesting that cAMP, PKA, casein kinase II, and cytosolic calcium signaling may oppose to the effect of ghrelin on the phosphorylation of GluN2B. Our findings suggest that 1) GluN2B is likely a molecular target of ghrelin and GHSR1a-driven signaling cascades, and 2) the ghrelin-mediated phosphorylation of GluN2B depends on Fyn activation under complex negative regulation by other second messengers.

Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis

“…However, treatment of GOAT −/− mice with acyl-ghrelin once daily for 7 days restored performance to WT levels [ 47 ]. These data suggest that acyl-ghrelin signalling is activating both neurogenic and other hippocampal pathways to support memory function and is consistent with previous studies identifying enhanced hippocampal long-term potentiation (LTP) [ 7 , 53 , 54 ], increased expression of GluA1-containing amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [ 55 ], as well as the phospho-GluN2B [ 56 ] and the NR2B subunit of the N-methyl-D-aspartate receptor (NMDA) receptor [ 57 ], in response to acyl-ghrelin. Our findings support a role for UAG in blocking acyl-ghrelin-mediated GHS-R1a signalling in the hippocampus [ 47 ].…”

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

“…Indeed, since its development, this probe has been used on numerous occasions in the identification of ghrelin binding sites in genetically engineered cells and in mouse brain tissue. [65][66][67][68] The brain areas accessible to ghrelin have been elucidated by systematically mapping the distribution of centrally or peripherally administered tracer 6 in the mouse brain, demonstrating uptake in GHSR expressing brain areas. [69][70][71][72] Further efforts utilized this probe to better illuminate the possible mechanisms by which circulating ghrelin accesses its receptor in the brain.…”

A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain

“…Therefore, we hypothesized that an SFK mediates the maintenance of latent sensitization. We tested this hypothesis by determining whether PP2, an inhibitor of Fyn and other SFKs (Mizuno et al, 2003;Li et al, 2017;Berrout and Isokawa, 2018) reverses the allodynia produced by the opioid antagonist naltrexone (NTX) in latent sensitization induced by inflammation with complete Freund's adjuvant (CFA) or by spared nerve injury (SNI).…”