Chloride channel opener
In general, mutations in various chloride channels throughout the human body can result in many pathologies, such as macular degeneration, myotonia, cystic fibrosis, and hyperekplexia.
The relative structural complexity of chloride channels, their varied roles in biological processes, and the problems associated with the development of drugs with high specificity emphasize the necessity for further research in this area.
[5] Several different intracellular transport channels, with varying functions, exist throughout the human body to facilitate routine upkeep and maintenance.
[7] Chloride (Cl-), the most abundant anion in the human body,[6][7] as well as Sodium (Na+) and Potassium (K+), determine the electrochemical potential across a cell.
Some functions of chloride channels include ion homeostasis, cell volume regulation, and modulation of electrical excitability.
[7] Chloride channels also partake in cell apoptosis caused by endoplasmic reticulum (ER) stress, in addition to their roles in modulation of membrane potential and gating anions.
CFTR chloride channels have important roles in various aspects of the human body, such as in fluid and electrolyte secretion within the intestines, pancreas, and sweat glands.
The calcium-activated chloride channel family (CaCCs) are present throughout a wide range of tissues, participating in several physiological processes including epithelial secretion, sensory transduction, and smooth muscle contraction.
[17] The ionotropic GABA-A and GABA-C receptors can be activated by GABA to open and allow entry of negatively chloride ions into a cell, playing a significant role in the control of neuronal excitability.
GABA-A receptors are GABA-gated anion channels which are involved in the function of rapid inhibitory synaptic transmission through the vertebrate CNS [18][28].
Alternatively, tonic GABA-A receptor-mediated inhibition results from an activation of extrasynaptic receptors by low concentrations of ambient GABA.
For example, epilepsy related sleep disturbances are believed to be partially caused by improper activation of the β3 GABA-A receptor subunit.
[16] GABA-A therapeutics are a related therapy that could potentially be treated or targeted by chloride ion channel opener drugs.
[6][7][11] The discovery of GABA-A receptors has allowed the scientific community to see that chloride channels could have a direct link to central nervous system (CNS) cell operation.
[22] One example of a common chloride channel activator which is used to treat both constipation caused by IBS (irritable bowel syndrome) as well as cystic fibrosis would be Lubiprostone.
[23] This drug is poorly absorbed following oral administration, until its eventual metabolization within the stomach and the small intestine (specifically the jejunum).
[19] As the technology used for the development of cation and anion gated channel targets is largely similar, many of the strategies used to do so can be applied interchangeably.
[27] Chloride gated channel opener mutations have been a major pharmacologic target, as dysfunction of this receptor results in common muscular diseases such as hyperekplexia and even depressive disorders.
A class of natural coumarin compounds, identified by scientists, is capable of correcting the defective chloride channel gating.
[28] The compound, which is a Chinese medicinal herb, was mixed with a cAMP (cyclic adenosine monophosphate) agonist and exposed to a mutation in question.
Due to its role in physiological processes such as neuronal network maturation and excitability, manipulation of the chloride channel has been linked to diseases such as epilepsy.
Though this approach could, in theory, be a solution, the lack of success in studies targeting calcium channels for this expressed purpose have been mostly abandoned [16][27].
Most notably, this lack of understanding results in difficulties in developing chloride channel modulators with a high level of specificity.
Regarding the future direction of chloride channel opener drug development, research will likely proceed to the exploration of applications outside of the realm of cystic fibrosis.
It has been observed that mutations in chloride channel proteins can result in a multitude of diseases and disorders beyond cystic fibrosis due to their importance in several biological processes.
