HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment

Johard, Helena A.D.; Omelyanenko, Anna; Gao, Fei; Zilberter, Misha; Dave, Zankruti; Abu-Youssef, Randa; Schmidt, Linnéa; Harisankar, Aditya; Vincent, C. Theresa; Walfridsson, Julian; Nelander, Sven; Harkany, Tibor; Blomgren, Klas; Andäng, Michael

doi:10.1158/1541-7786.mcr-20-0292

Cited by 7 publications

(11 citation statements)

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“…These results indicate that, in addition to -and perhaps as a consequence of -a direct effect on NSC proliferation, a dysfunction in HCN subunits might also result in a dysregulated balance between neurogenesis and gliogenesis. A recent study found that both the application of ZD7288, or of the less specific Ih blocker Cs + , onto NSC cultures reduced the fraction of cells showing spontaneous Ca 2+ oscillations (23). Using slightly different experimental conditions such as a shorter observation time, we did not find systematic changes in Ca 2+ oscillations in our experiments with cultured rat NSCs upon ZD7288 application (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 59%

“…HCN channels are part of an evolutionarily old and conserved family of ion channels (55) that are expressed in different cell types with proliferative potential (56,57). A comparison of our HCNsubunit expression analyses with those of other studies and databases of embryonic mouse brain, stem cells, and induced human pluripotent stem cells has consistently revealed HCN3 to be the most abundant subunit (21,23,27,56,57). In addition to HCN3, the data also implicate HCN1 and HCN4 as potential HCN subtypes in the developing mouse and human fetal cerebral cortices (SI Appendix, Figs.…”

Section: Discussionmentioning

confidence: 63%

“…3) is attributable to a severe reduction in cell-cycle speed, which scRNAseq indicates is primarily due to G1 phase lengthening, ultimately causing depletion of the neural progenitor pool and, as a consequence, microcephaly. Loss of functional HCN channels in NSCs affected the membrane potential (23), which is more depolarized in cycling cells than in cell cycleexiting cells (3). Together, the data indicate that Ih, which contributes to rhythmic activity in many cell types likely including NSCs (23), also helps control the entry into or exit from the cell cycle in neural progenitors.…”

Section: Discussionmentioning

confidence: 90%

“…When active in stem cells, HCN channels could contribute to membrane depolarization or membrane voltage oscillations throughout the cell cycle. As pharmacological inhibition of HCN channels in cultured embryonic stem cells affected proliferation and differentiation (21,22), neural stem and progenitor cells could likewise be affected by impaired function of HCN channels (23).…”

Section: Introductionmentioning

confidence: 99%

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Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

Schlusche¹,

Vay²,

Kleinenkuhnen³

et al. 2021

Preprint

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The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN)-channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN-channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN-channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a novel role for HCN-channel subunits as a part of a general mechanism influencing cortical development in mammals.Significance StatementImpaired cell cycle regulation of neural stem and progenitor cells can affect cortical development and cause microcephaly. During cell cycle progression, the cellular membrane potential changes through the activity of ion channels and tends to be more depolarized in proliferating cells. HCN channels, which mediate a depolarizing current in neurons and cardiac cells, are linked to neurodevelopmental diseases, also contribute to the control of cell-cycle progression and proliferation of neuronal precursor cells. In this study, HCN-channel deficiency during embryonic and fetal brain development resulted in marked microcephaly of mice designed to be deficient in HCN-channel function in dorsal forebrain progenitors. The findings suggest that HCN-channel subunits are part of a general mechanism influencing cortical development in mammals.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

Schlusche¹,

Vay²,

Kleinenkuhnen³

et al. 2021

Preprint

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show abstract

“…Furthermore, systemic, or local administration of ZD7288 suppresses neuropathic pain behavior as well as abnormal spontaneous firing in injured nerve fibers in rats, supporting the accumulating evidence that increased HCN channel activity is responsible for neuropathic pain ( Chaplan et al, 2003 ; Lee et al, 2005 ; Luo et al, 2007 ; Ding et al, 2018 ). Moreover, HCN channel inhibition with ZD7288 provides protection for neural stem cells during radiotherapy, suggesting new therapeutic strategies against neurocognitive damage caused by chemotherapy and radiotherapy in cancer patients ( Johard et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

Zhong

Darmani

2021

Front. Pharmacol.

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Subtypes (1–4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i.p.) and 83.3% at 10 µg (i.c.v.). HCN channel subtype (1–4) expression was assessed using immunohistochemistry in the least shrew brainstem dorsal vagal complex (DVC) containing the emetic nuclei (area postrema (AP), nucleus tractus solitarius and dorsal motor nucleus of the vagus). Highly enriched HCN1 and HCN4 subtypes are present in the AP. A 1 mg/kg (i.p.) dose of ZD7288 strongly evoked c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem DVC, but not in the in the enteric nervous system in the jejunum, suggesting a central contribution to the evoked vomiting. The ZD7288-evoked c-Fos expression exclusively occurred in tryptophan hydroxylase 2-positive serotonin neurons of the dorsal vagal complex, indicating activation of serotonin neurons may contribute to ZD7288-induced vomiting. To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca2+ channel (nifedipine); store-operated Ca2+ entry (MRS 1845); T-type Ca2+ channel (Z944), IP3R (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. All tested antiemetics except sulpride attenuated ZD7288-evoked vomiting to varying degrees. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca2+ signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment.

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Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner

Zhang,

Liu,

Sun

et al. 2023

Cell Reports

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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment

Abstract: during cancer treatment. neural stem cells and is a selective target for neuroprotection HCN channel activity balances quiescence and proliferation in Updated version

Cited by 7 publications

References 54 publications

Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva)

Hyperpolarization-activated cyclic nucleotide-gated cation channel 3 promotes HCC development in a female-biased manner

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