Mechanism of Action
Aconitine can interact with the voltage-dependent sodium-ion channels. These sodium channels are bound in the membrane of cells in excitable tissues, such as muscles and neurons. The channels are highly selective for sodium-ions. They open very fast to depolarize the membrane, and close to repolarize the membrane. Aconitine binds to the receptor at the neurotoxin binding site 2 on the alpha-subunit of the channel protein. This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium-influx. As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage. In neurons, aconitine increases the permeability of the membrane for sodium-ions, resulting in a huge sodium-influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium-ions increases fast, resulting in a potassium-refflux to release the positive charge out of the cell. Not only the permeability for potassium-ions but also the permeability for calcium-ions increases as a result of the depolarization of the membrane. A calcium-influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential. Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0,1 microM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension. Action potentials are generated more often at this concentration. At higher concentration (0,3-3microM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0,3-30 microM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.
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