Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels
Open accessAbstract
The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQ signalling is likely a common pathway utilized by the nervous system. The gut-derived orexigenic hormone, ghrelin, enhances neuronal firing in the substantia nigra pars compacta. This study shows that ghrelin enhances firing of nigral dopaminergic neurons by a novel mechanism in which activation of the PLC/PKC pathway inhibits Kv7 channels.
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Ghrelin participates in the regulation of motor functions by modulating dopaminergic neuronal excitability within the substantia nigra.
“Ghrelin participates in the regulation of motor functions by modulating the dopaminergic neuronal excitability within the SN.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [559]
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Self-citation
- Authors
- Shi, L., Bian, X., Qu, Z., Ma, Z., Zhou, Y., Wang, K., Jiang, H., & Xie, J.
- Affiliations
- Qingdao University (CN)
- Peking University (CN)
- Corresponding author
- Wang, KeWei
- Jiang, Hong
- Xie, Junxia
- Venue
- Nature Communications
- Published
- 2013-02-05
- Volume
- 4
- Issue
- 1
- Pages
- 1435-1435
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2019734375
- Cited by
- 103
- References
- 59
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 15 · 2014: 4 · 2013: 6
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Natural Science Foundation of China (81170207, 30930036, 2011CB504100, 30970919, 81000552)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- ghrelin, neuronal excitability, substantia nigra pars compacta, dopaminergic neurons, GHS-R1a, dopamine release, striatum, dystonia, catalepsy, XE991, gut-brain signaling, orexigenic peptides
- MeSH terms
- Action Potentials, Animals, Catalepsy, Dopamine, Ganglia, Spinal, Haloperidol, Injections, Intraventricular, Mice, Transgenic, Nystatin, Type C Phospholipases, Substantia Nigra, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Pyramidal Cells, Potassium Channel Blockers, Mice, Rats, KCNQ Potassium Channels, Ghrelin, Receptors, Ghrelin, CA1 Region, Hippocampal, Dopaminergic Neurons
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