Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Previous evidence suggests that GHS-R1a is expressed in the hippocampus (6,(27)(28)(29), but the subcellular localization of GHS-R1a in hippocampal cells has not been studied. Primary hippocampal neurons were immunolabeled at 15 d in vitro (DIV) for endogenous GHS-R1a.…”

Section: Ghs-r1amentioning

confidence: 99%

“…Organotypic slice cultures were infected with GluA1-GFP at 1 or 2 DIV, and the electrophysiology recordings were performed at 3 or 4 DIV. Organotypic hippocampal slices were treated with 1 μM ghrelin, a concentration of ghrelin that was previously found to result in a maximal effect on the neuronal firing rate of nigral dopaminergic neurons, and in vivo dopamine release in the striatum (29). Organotypic slice cultures were treated for 20 h with the purpose of mimicking fasting, a nutritional status which has been associated with a prolonged increase in ghrelin circulating levels (4).…”

Section: Ghs-r1a Activation Enhances Excitatory Synaptic Transmission Bymentioning

confidence: 99%

Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

Ribeiro

Catarino

Santos

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognitionenhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.T he appetite-stimulating peptide ghrelin is a 28-aa peptide predominantly produced by X/A-like cells in the oxyntic glands of the stomach as well as in the intestine (1), and secreted into the blood stream. This peptide promotes pituitary growth hormone secretion, through activation of the growth hormone secretagogue type 1a receptor (GHS-R1a) or ghrelin receptor (2). Additionally, ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization (3). Plasma ghrelin levels rise before meals and decrease thereafter (4), a pattern which is consistent with the implication of ghrelin in preprandial hunger and meal initiation. Ghrelin is secreted into the circulation and crosses the blood-brain barrier (5, 6), but there is also evidence for ghrelin synthesis locally in the brain (2,7,8). The GHS-R1a receptor mRNA was initially found in the hypothalamus and in the pituitary gland (9), and later detected in the hippocampus (10). GHS-R1a is a G protein-coupled seventransmembrane domain receptor (3), which can signal through guanine nucleotide-binding protein (G protein) subunit alpha 11 (Gq class) to activate phosphatidylinositol-specific phospholipase C, generating 1,4,5-triphosphate (IP 3 ) responsible for Ca 2+ intracellular release from endoplasmic reticulum, and diacylglicerol, which in turn activates protein kinase C (PKC) (11). Ghrelin receptor activation is also coupled to the phosphatidylinositol 3 (PI3)-kinase signaling cascade in different cellular systems through a pertussis toxin-sensitive G protein (G i/o α) (11), and to protein kinase A (PKA) in isolated hypothalamic neurons, modulating N-type Ca 2+ channels (12).T...

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“…Midbrain DA neurons have been found to also have KCNQ potassium channels that contribute to their tonic spontaneous activity, and during hyperpolarization these neurons display a typical sag in voltage [31]. Here, we injected negative current to hyperpolarize the membrane of Atoh1-induced neurons (Fig.…”

Section: Functional Characterization Of Atoh1-induced Da Neuronsmentioning

confidence: 99%

Proneural Transcription Factor Atoh1 Drives Highly Efficient Differentiation of Human Pluripotent Stem Cells Into Dopaminergic Neurons

Sagal

Zhan

et al. 2014

Stem Cells Translational Medicine

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Human pluripotent stem cells (PSCs) are a promising cell resource for various applications in regenerative medicine. Highly efficient approaches that differentiate human PSCs into functional lineagespecific neurons are critical for modeling neurological disorders and testing potential therapies. Proneural transcription factors are crucial drivers of neuron development and hold promise for driving highly efficient neuronal conversion in PSCs. Here, we study the functions of proneural transcription factor Atoh1 in the neuronal differentiation of PSCs. We show that Atoh1 is induced during the neuronal conversion of PSCs and that ectopic Atoh1 expression is sufficient to drive PSCs into neurons with high efficiency. Atoh1 induction, in combination with cell extrinsic factors, differentiates PSCs into functional dopaminergic (DA) neurons with >80% purity. Atoh1-induced DA neurons recapitulate key biochemical and electrophysiological features of midbrain DA neurons, the degeneration of which is responsible for clinical symptoms in Parkinson's disease (PD). Atoh1-induced DA neurons provide a reliable disease model for studying PD pathogenesis, such as neurotoxin-induced neurodegeneration in PD. Overall, our results determine the role of Atoh1 in regulating neuronal differentiation and neuron subtype specification of human PSCs. Our Atoh1-mediated differentiation approach will enable large-scale applications of PD patient-derived midbrain DA neurons in mechanistic studies and drug screening for both familial and sporadic PD. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:888-898

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Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

Cited by 96 publications

References 58 publications

Nesfatin-1 acts on the dopaminergic reward pathway to inhibit food intake

Nesfatin-1 acts on the dopaminergic reward pathway to inhibit food intake

Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

Proneural Transcription Factor Atoh1 Drives Highly Efficient Differentiation of Human Pluripotent Stem Cells Into Dopaminergic Neurons

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