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Ghrelin receptor activity amplifies hippocampal N ‐methyl‐ d ‐aspartate receptor‐mediated postsynaptic currents and increases phosphorylation of the GluN1 subunit at Ser896 and Ser897
Author(s) -
Muniz Brandon G.,
Isokawa Masako
Publication year - 2015
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13107
Subject(s) - ghrelin , endocrinology , medicine , growth hormone secretagogue receptor , nmda receptor , hippocampal formation , hippocampus , agonist , chemistry , receptor , inverse agonist , biology , hormone
Although ghrelin and its cognate receptor growth hormone secretagogue receptor ( GHSR 1a) are highly localized in the hypothalamic nuclei for the regulation of metabolic states and feeding, GHSR 1a is also highly localized in the hippocampus, suggesting its involvement in extra‐hypothalamic functions. Indeed, exogenous application of ghrelin has been reported to improve hippocampal learning and memory. However, the underlying mechanism of ghrelin regulation of hippocampal functions is poorly understood. Here, we report ghrelin‐promoted phosphorylation of GluN1 and amplified N ‐methyl‐ d ‐aspartate receptor ( NMDAR )‐mediated excitatory postsynaptic currents in the CA 1 pyramidal cells of the hippocampus in slice preparations. The ghrelin‐induced responses were sensitive to a GHSR 1a antagonist and inverse agonist, and were absent in GHSR 1a homozygous knock‐out mice. These results indicated that activation of GHSR 1a was critical in the ghrelin‐induced enhancement of the NMDAR function. Interestingly, heterozygous mouse hippocampi were also insensitive to ghrelin treatment, suggesting that a slight reduction in the availability of GHSR 1a may be sufficient to negate the effect of ghrelin on GluN1 phosphorylation and NMDAR channel activities. In addition, NMDAR ‐mediated spike currents, which are of dendritic origin, were blocked by the GHSR 1a antagonist, suggesting the presence of GHSR 1a on the pyramidal cell dendrites in physical proximity to NMDAR . Together with our findings on the localization of GHSR 1a in the CA 1 region of the hippocampus, which was shown by fluorescent ghrelin binding, immunoreactivity, and enhanced green fluorescent protein reporter gene expression, we conclude that the activation of GHSR 1a favours rapid modulation of the NMDAR ‐mediated glutamatergic synaptic transmission by phosphorylating GluN1 in the hippocampus.