ion channel


What are Ion Channels?

Ion channels allow the movement of charged particles, known as ions, across cell membranes. Ion channels function in a variety of biological pathways including the firing of neurons and muscle cells and the activation of immune cells.

Overview

Ion channels are used to restore the balance of ions across a membrane. When open, ion channels allow charged molecules to move from an area of high concentration to low concentration without using energy. Ion channels serve as a counterbalance to active transport, a process whereby a cell uses energy to actively pump ions and other charged molecules across a membrane in order to establish ion gradients or alter the pH of an organelle to activate enzymes. There are two major types of ion channels:

  • Voltage-gated ion channels
  • Ligand-gated ion channels

When ions are present in a higher concentration on one side of a membrane than the other, a difference in voltage occurs across that membrane, creating a membrane potential. Voltage-gated ion channels open in response to a change in membrane potential, allowing the ions to move from the side of the membrane with the higher ion concentration to the side with the lower ion concentration.

Ligand-gated ion channels rely on the binding of a small molecule to the channel. The small molecule binding causes a change in the channel protein, opening the pore for the ions to travel through. As with voltage-gated ion channels, when ligand-gated ion channels open ions move from the side of the membrane with the higher ion concentration to the side with the lower ion concentration.

When targeted by therapeutics, ion channels are either inhibited, preventing the flow of ions, or held constitutively open by the action of agonists, preventing the accumulation of ions on one side of the membrane. The desired activity of the ion channel modulator depends on the disease being targeted.

Existing Products

There are several ion channel modulators currently in use. Examples are included in the table below.

Channel Type Target Name Development Status
Voltage-gated Ca2+ channel Multiple FDA approved anti-hypertensives
Na+ channel Multiple FDA approved products including local anaesthetics and anticonvulsants
K+ channel Multiple sulfonylureas approved for diabetes
Ligand-gated Glutamate-gated chloride channel Ivermectin, FDA approved for onchocerciasis and in use for the treatment of lymphatic filariasis
Acetylcholine-gated chloride channels Levamisole, pyrantal, and tribendamadine (China only), for treatment of helminth infections

Multiple FDA approved products for the treatment of tobacco dependence

Ion Channel Modulators as Non-Neglected Tropical Disease Therapeutics

Ion channel inhibitors are used to treat a wide range of conditions including:

  • Hypertension
  • Pain
  • Convulsions
  • Diabetes
  • Tobacco dependence

The most well-known and widely-used ion channel inhibitors are the calcium channel inhibitors used to treat high blood pressure. The movement of calcium across cell membranes causes muscle contractions. While this is a normal biological process, contraction of the muscles of the circulatory system can exacerbate the condition of patients with high blood pressure or hypertension. Calcium channel blockers are used in patients with hypertension to reduce contraction of the smooth muscles of the arteries, allowing the arteries to dilate to reduce blood pressure.

Ion Channel Modulators as Neglected Tropical Disease Therapeutics

Ion channel inhibitors are used to treat parasitic worm infections including:

  • Onchocerciasis
  • Lymphatic filariasis
  • Ascariasis
  • Hookworm
  • Schistosomiasis

Ivermectin is a glutamate-gated chloride channel inhibitor that is widely used in mass drug administration programs in the developing world to treat infections with parasitic worms that cause onchocerciasis and lymphatic filariasis.1,2 Ivermectin is also used widely in veterinary medicine for the treatment of worm infections.3The drug is believed to work in these organism by inhibiting glutamate-gated chloride channels, which are only found in invertebrates, allowing these drugs to selectively target parasitic worms over their human hosts.4 Disruption of the flow of chloride causes paralysis and starvation of the worm leading to death.

Levamisole and pyrantal pamoate can be used to treat the soil transmitted helminths ascariasis and hookworm, but are not widely used. Tribendamadine is used to treat ascariasis in China but has not been extensively evaluated or used outside of China. All three of these products are agonists of acetylcholine-gated chloride channels.5 These drugs force the chloride channels to remain open rather inhibiting them; the resulting imbalance of chloride ions results in death of the worms.

Praziquantel is the only on market drug for the treatment of schistosomiasis. Although the mechanism of action of praziquantel is not entirely clear, it is believed that the drug inhibits calcium channels on the parasite.6 More research is needed to understand if inhibition of calcium channels is the primary mechanism of action of praziquantel or part of a multi-target mechanism.

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References

  1. WHO NTD Report 2010
  2. Keiser J and Utzinger J (2010) “The drugs we have and the drugs we need against major helminth infections.” Advances in Parasitology 73: 197-229.
  3. Raymond V and Sattelle DB (2002) “Novel animal-health drug targets from ligand-gated chloride channels.” Nature Reviews: Drug Discovery 1: 427-436.
  4. Geary TG (2005) “Ivermectin 20 years on: maturation of a wonder drug.” TRENDS in Parasitology 21: 530-532.
  5. Hu Y et al. (2009) The New Anthelmintic Tribendimidine is an L-type (Levamisole and Pyrantel) Nicotinic Acetylcholine Receptor Agonist. PLoS NTD 3: e499.
  6. Doenhoff MJ et al. (2008) “Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis.” Curr Opin Infect Dis 21: 659-667.

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