Retracted: K ATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin
Key points Ghrelin, a hunger signalling peptide derived from the peripheral tissues, overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. Using in vivo and in vitro electrophysiological techniques, we show that ghrelin hyperp...
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Published in | The Journal of physiology Vol. 593; no. 17; pp. 3973 - 3989 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.09.2015
|
Online Access | Get full text |
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Summary: | Key points
Ghrelin, a hunger signalling peptide derived from the peripheral tissues, overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding.
Using
in vivo
and
in vitro
electrophysiological techniques, we show that ghrelin hyperpolarizes neurons and inhibits currents evoked by leptin and CCK‐8.
Administering a K
ATP
channel antagonist or silencing Kir6.2, a major subunit of the K
ATP
channel, abolished ghrelin inhibition.
The inhibitory actions of ghrelin were also abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3‐kinase (PI3K) or extracellular signal‐regulated kinase 1 and 2 (Erk1/2) small interfering RNA.
Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin.
These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating K
ATP
conductance via the growth hormone secretagogue receptor subtype 1a–G
αi
–PI3K–Erk1/2–K
ATP
pathway.
This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways.
Abstract
Ghrelin is the only known hunger signal derived from the peripheral tissues. Ghrelin overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. The mechanisms by which ghrelin reduces the sensory signals evoked by anorexigenic hormones, which act via the vagus nerve to stimulate feeding, are unknown. Patch clamp recordings of isolated rat vagal neurons show that ghrelin hyperpolarizes neurons by activating K
+
conductance. Administering a K
ATP
channel antagonist or silencing Kir6.2, a major subunit of the K
ATP
channel, abolished ghrelin inhibition
in vitro
and
in vivo
. Patch clamp studies show that ghrelin inhibits currents evoked by leptin and CCK‐8, which operate through independent ionic channels. The inhibitory actions of ghrelin were abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3‐kinase (PI3K) or extracellular signal‐regulated kinase 1 and 2 (Erk1/2) small interfering RNA.
In vivo
gene silencing of PI3K and Erk1/2 in the nodose ganglia prevented ghrelin inhibition of leptin‐ or CCK‐8‐evoked vagal firing. Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin. These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating K
ATP
conductance via the growth hormone secretagogue receptor subtype 1a–G
αi
–PI3K–Erk1/2–K
ATP
pathway. The resulting hyperpolarization renders the neurons less responsive to signals evoked by anorexigenic hormones. This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways. |
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ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/JP270788 |