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17β-Estradiol Regulation of T-Type Calcium Channels in Gonadotropin-Releasing Hormone Neurons
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T-type calcium channels are responsible for generating low-threshold spikes that facilitate burst firing and neurotransmitter release in neurons. Gonadotropin-releasing hormone (GnRH) neurons exhibit burst firing, but the underlying conductances are not known. Previously, we found that 17β-estradiol (E2) increases T-type channel expression and excitability of hypothalamic arcuate nucleus neurons. Therefore, we used ovariectomized oil- or E2-treated EGFP (enhanced green fluorescent protein)–GnRH mice to explore the expression and E2 regulation of T-type channels in GnRH neurons. Based on single-cell reverse transcriptase-PCR and real-time PCR quantification of the T-type channel α 1 subunits, we found that all three subunits were expressed in GnRH neurons, with expression levels as follows: Cav3.3 ≥ Cav3.2 > Cav3.1. The mRNA expression of the three subunits was increased with surge-inducing levels of E2 during the morning. During the afternoon, Cav3.3 mRNA expression remained elevated, whereas Cav3.1 and Cav3.2 were decreased. The membrane estrogen receptor agonist STX increased the expression of Cav3.3 but not Cav3.2 in GnRH neurons. Whole-cell patch recordings in GnRH neurons revealed that E2 treatment significantly augmented T-type current density at both time points and increased the rebound excitation during the afternoon. Although E2 regulated the mRNA expression of all three subunits in GnRH neurons, the increased expression combined with the slower inactivation kinetics of the T-type current indicates that Cav3.3 may be the most important for bursting activity associated with the GnRH/LH (luteinizing hormone) surge. The E2-induced increase in mRNA expression, which depends in part on membrane-initiated signaling, leads to increased channel function and neuronal excitability and could be a mechanism by which E2 facilitates burst firing and cyclic GnRH neurosecretion.
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“Furthermore, activation of GPER by its selective ligand STX in mouse GnRH neurons controlled the expression and activity of cation channels involved in burst firing and membrane hyperpolarization42,43, indicating the E2 has multiple pathways and receptors to control GnRH neuronal excitability, gene expression, and peptide release.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [42]
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Metadata
- Authors
- Zhang, C., Bosch, M. A., Rick, E. A., Kelly, M. J., & Rønnekleiv, O. K.
- Affiliations
- Oregon Health & Science University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-08-26
- Volume
- 29
- Issue
- 34
- Pages
- 10552-10562
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2774467
- OpenAlex
- W1984310913
- Cited by
- 104
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 1 · 2019: 6 · 2018: 8 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 6 · 2013: 12 · 2012: 8
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 68098, R56DK068098, R01DK068098)
- National Institute of Neurological Disorders and Stroke (NS43330, R56NS038809, NS 38809, R01NS038809, R01NS043330)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- 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
- Keywords
- estradiol, T-type calcium channels, GnRH neurons, Cav3.3, Cav3.2, Cav3.1, burst firing, neuronal excitability, luteinizing hormone surge, estrogen receptor signaling, hypothalamic arcuate nucleus, estrogen regulation of gene expression, rebound excitation
- MeSH terms
- Analysis of Variance, Animals, Arcuate Nucleus of Hypothalamus, Electric Stimulation, Estradiol, Estrogens, Female, Gene Expression Regulation, Gonadotropin-Releasing Hormone, Membrane Potentials, Mice, Transgenic, Neurons, Nickel, Ovariectomy, RNA, Messenger, Drug Delivery Systems, Patch-Clamp Techniques, Calcium Channels, T-Type, Estradiol Congeners, Green Fluorescent Proteins, Mice, In Vitro Techniques
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