The impact of hyperpolarization-activated cyclic nucleotide-gated (HCN) and voltage-gated potassium KCNQ/Kv7 channels on primary microglia function.
Animals
Calcium
/ metabolism
Cell Proliferation
/ drug effects
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
/ antagonists & inhibitors
Microglia
/ drug effects
Phagocytosis
/ drug effects
Potassium Channel Blockers
/ pharmacology
Potassium Channels, Voltage-Gated
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
RNA Interference
Rats
Rats, Wistar
Cerebral ischemia
Ih-current
Ion channel
Microglia activation
Microglia phenotype
Migration
Neuroinflammation
Phagocytosis
Voltage sensor probes
XE-991
ZD7288
siHCN2
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
06 Apr 2020
06 Apr 2020
Historique:
received:
16
01
2020
accepted:
18
03
2020
entrez:
7
4
2020
pubmed:
7
4
2020
medline:
7
1
2021
Statut:
epublish
Résumé
Microglia are essential to maintain cell homeostasis in the healthy brain and are activated after brain injury. Upon activation, microglia polarize towards different phenotypes. The course of microglia activation is complex and depends on signals in the surrounding milieu. Recently, it has been suggested that microglia respond to ion currents, as a way of regulating their activity and function. Under the hypothesis that HCN and KCNQ/Kv7 channels impact on microglia, we studied primary rat microglia in the presence or absence of specific pharmacological blockade or RNA silencing. Primary microglia expressed the subunits HCN1-4, Kv7.2, Kv7.3, and Kv7.5. The expression of HCN2, as well as Kv7.2 and Kv7.3, varied among different microglia phenotypes. The pharmacological blockade of HCN channels by ZD7288 resulted in cell depolarization with slowly rising intracellular calcium levels, leading to enhanced survival and reduced proliferation rates of resting microglia. Furthermore, ZD7288 treatment, as well as knockdown of HCN2 RNA by small interfering RNA, resulted in an attenuation of later microglia activation-both towards the anti- and pro-inflammatory phenotype. However, HCN channel inhibition enhanced the phagocytic capacity of IL4-stimulated microglia. Blockade of Kv7/KCNQ channel by XE-991 exclusively inhibited the migratory capacity of resting microglia. These observations suggest that the HCN current contributes to various microglia functions and impacts on the course of microglia activation, while the Kv7/KCNQ channels affect microglia migration. Characterizing the role of HCN channels in microglial functioning may offer new therapeutic approaches for targeted modulation of neuroinflammation as a hallmark of various neurological disorders.
Sections du résumé
BACKGROUND
BACKGROUND
Microglia are essential to maintain cell homeostasis in the healthy brain and are activated after brain injury. Upon activation, microglia polarize towards different phenotypes. The course of microglia activation is complex and depends on signals in the surrounding milieu. Recently, it has been suggested that microglia respond to ion currents, as a way of regulating their activity and function.
METHODS AND RESULTS
RESULTS
Under the hypothesis that HCN and KCNQ/Kv7 channels impact on microglia, we studied primary rat microglia in the presence or absence of specific pharmacological blockade or RNA silencing. Primary microglia expressed the subunits HCN1-4, Kv7.2, Kv7.3, and Kv7.5. The expression of HCN2, as well as Kv7.2 and Kv7.3, varied among different microglia phenotypes. The pharmacological blockade of HCN channels by ZD7288 resulted in cell depolarization with slowly rising intracellular calcium levels, leading to enhanced survival and reduced proliferation rates of resting microglia. Furthermore, ZD7288 treatment, as well as knockdown of HCN2 RNA by small interfering RNA, resulted in an attenuation of later microglia activation-both towards the anti- and pro-inflammatory phenotype. However, HCN channel inhibition enhanced the phagocytic capacity of IL4-stimulated microglia. Blockade of Kv7/KCNQ channel by XE-991 exclusively inhibited the migratory capacity of resting microglia.
CONCLUSION
CONCLUSIONS
These observations suggest that the HCN current contributes to various microglia functions and impacts on the course of microglia activation, while the Kv7/KCNQ channels affect microglia migration. Characterizing the role of HCN channels in microglial functioning may offer new therapeutic approaches for targeted modulation of neuroinflammation as a hallmark of various neurological disorders.
Identifiants
pubmed: 32248813
doi: 10.1186/s12974-020-01779-4
pii: 10.1186/s12974-020-01779-4
pmc: PMC7132998
doi:
Substances chimiques
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
0
Potassium Channel Blockers
0
Potassium Channels, Voltage-Gated
0
Pyrimidines
0
ICI D2788
133059-99-1
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
100Subventions
Organisme : Marga und Walter Boll-Stiftung
ID : 210-10-15
Organisme : Universität zu Köln
ID : 345/2018
Organisme : Deutscher Akademischer Austauschdienst
ID : 57393537
Organisme : Science and Technology Development Center, Ministry of Education
ID : III41005
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