Tanshinone IIA selectively enhances hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel instantaneous current.
Tanshinone IIA, one of the main active components from the Chinese herb Danshen, is widely used to treat cardiovascular diseases in Asian countries, especially in China. To further elucidate its heart rate-reducing and anti-ischemic mechanisms, here we investigated the effects of tanshinone IIA on hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels expressed in Xenopus oocytes using two-electrode voltage clamp techniques. When applied to the extracellular solution, 100 microM tanshinone IIA caused a slowing of activation and deactivation and an increase of minimum open probabilities (from 0.06 +/- 0.01 to 0.29 +/- 0.03, P<0.05) in HCN2 channels without shifting the voltage dependence of channel activation. Tanshinone IIA potently enhanced the amplitude of voltage-independent current (instantaneous current) of HCN2 at -90 mV in a concentration-dependent manner with an EC(50) of 107 microM. Similar but 2.3-fold less sensitivity to tanshinone IIA was observed in the HCN1 subtype. More significant effect on HCN2 and MiRP1 co-expression was observed. In conclusion, tanshinone IIA changed HCN channel gating by selectively enhancing the instantaneous current (one population of HCN channels), which resulted in the corresponding increment of minimum open probabilities, slowing channel activation and deactivation processes with little effect on the voltage-dependent current (another population of HCN channels).
Liang
Qiansheng
Q
Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. liangqs@tjh.tjmu.edu.cn
Yang
Le
L
Wang
Zhaohua
Z
Huang
Sufang
S
Li
Shusheng
S
Yang
Guangtian
G
D045784:Abietanes; D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000187:drug effects* / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009865:Oocytes; D010616:Phenanthrenes / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D014162:Transfection; D014982:Xenopus laevis
D045784:Abietanes; D054815:Cyclic Nucleotide-Gated Cation Channels; D004365:Drugs, Chinese Herbal; C578665:HCN1 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D010616:Phenanthrenes; D015221:Potassium Channels; C021751:tanshinone