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17β-estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-current in Female Mice

17β-estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-current in Female Mice

Kristie Conde, Troy A Roepke

Neuroendocrinology. 2019 Sep 5;10.1159/000503146.

PMID: 31484184

Abstract:

Obesity and anorexia result in dysregulation of the hypothalamic-pituitary-gonadal axis, negatively impacting reproduction. Ghrelin, secreted from the stomach, potentially mediates negative energy states and neuroendocrine control of reproduction by acting through the growth hormone secretagogue receptor (GHSR). GHSR is expressed in hypothalamic arcuate (ARC) Kisspeptin/Neurokinin B (Tac2)/Dynorphin (KNDy) neurons. Ghrelin is known to inhibit the M-current produced by KCNQ channels in other ARC neurons. In addition, we have shown 17-estradiol (E2) increases Ghsr expression in KNDy neurons 6-fold and increases the M-current in NPY neurons. We hypothesize that E2 increases GHSR expression in KNDy neurons to increase ghrelin sensitivity during negative energy states. Furthermore, we suspect ghrelin targets the M-current in KNDy neurons to control reproduction and energy homeostasis. We utilized ovariectomized (OVX) Tac2-EGFP adult female mice, pre-treated with estradiol benzoate (EB) or oil vehicle and performed whole-cell-patch-clamp recordings to elicit the M-current in KNDy neurons using standard activation protocols in voltage-clamp. Using the selective KCNQ channel blocker XE-991 (40 M) to target the M-current, oil- and EB-treated mice showed a decrease in the maximum peak current by 75.7 ± 13.8 pA (n=10) and 68.0 ± 14.7 pA (n=11), respectively. To determine the actions of ghrelin on the M-current, ghrelin was perfused (100 nM) in oil- and EB-treated mice resulting in the suppression of the maximum peak current by 58.5 ± 15.8 pA (n=9) and 59.2 ± 11.9 pA (n=9), respectively. KNDy neurons appeared more sensitive to ghrelin when pre-treated with EB, revealing that ARC KNDy neurons are more sensitive to ghrelin during states of high E2.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP122955424	XE-991		122955-42-4	Price

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