Ion Channels as Drug Target in the Clinic

Editorial

Ion channels are pore-forming proteins, located in the plasma membrane of almost all living cells. These protein complexes are often highly selectively allowing the flow of particular inorganic ions, primarily sodium (Na⁺), potassium (K⁺), calcium (Ca²⁺) or chloride (Cl^-) through aqueous pores across the lipid bilayer. Ion channels play a vital role in physiological processes such as muscle contraction, neuronal signaling, and nutrient transport and therefore human life would not exist without these pore-forming proteins. Likewise, these proteins are functional in the membranes of intracellular organelles such as the endoplasmic reticulum and mitochondria [1,2].

The movements of ions through their pores create an electrical current and these signals permit crucial functions such as the brain to receive and process information, the heart to beat and muscles to work [1]. In other words, they play main roles in very important physiological and pathological processes. Therefore, ion channels serve as a drug target in many important diseases. This manuscript will highlight the therapeutic agents that target ion channels and are currently used in the clinic to treat vital diseases and disorders.

Ion Channels as Drug Target in Cardiovascular System

Cardiovascular diseases are still the number one cause of death globally. Certainly, to maintain normal action potential duration and vascular tone, cardiovascular ion channels are required. Therefore, cardiovascular ion channels represent a critical target in clinic as a therapeutic target to treat important diseases such as arrhythmias, angina and hypertension.

In vascular smooth muscle cells, ion channels play a crucial role in the regulation of vascular tone (contractile activity). Opening of potassium channels causes’ potassium efflux and subsequently, hyperpolarizing the membrane potential which leads to vasodilation. Next, the closer of potassium channels depolarize the cells then activation of voltage gated calcium channels triggers the calcium release from intracellular stores which initiates the contraction [3-6].

Hypertension, which is high blood pressure and a major health problem, can lead to atherosclerosis, heart attack, stroke, enlarged heart and kidney damage. Ion channel agonist or antagonist through theirs vasodilator effect are used in the clinic to treat hypertension. Voltage-gated calcium channels (L-type) are targeted by various drugs (blockers) such as verapamil, amlodipine and nifedipine to treat hypertension [7]. Likewise, potassium channel activator, diazoxide, which target ATP-sensitive potassium (K_ATP) channels, is used as a vasodilator in the treatment of acute hypertension [1].

Atheromatous plaques gradually narrow the arteries with increasing age which cause obstruction to blood flow and finally symptoms of angina pectoris. Calcium channel blockers (voltagegated, L-type), such as verapamil, amlodipine, and diltiazem are used treat angina [8]. Similarly, nicorandil, which is K_ATP channel agonist and vasodilator, is used to treat angina [1].

An action potential is a transient, regenerating change in membrane potential that permits a wave of electrical excitation to pass along the plasma membrane of electrically excitable cells. Action potential consists of two major phases; depolarization and repolarization [9]. The heart rhythm abnormality (cardiac arrhythmias) occurs when the electrical impulses that coordinate the heartbeats don’t work appropriately. Ion channels, which are the key player in regulation of generating the action potential and heart rhythm, are targeted to treat cardiac arrhythmias.

Antiarrhythmic drugs are classified by their effects on the cardiomyocyte action potential and are mostly ion channel blockers [10,11]. As an example, these agents target L-type calcium channels (verapamil), voltage-dependent sodium channel (lidocaine) and amiodarone which block the potassium and sodium channels [10,11]. Development of new compounds to treat cardiac arrhythmia is necessary to improve the efficacy and prevent proarrhythmic effects (life-threatening arrhythmias) of the classic antiarrhythmic agents [11,12].

Ion Channels as Drug Target in Neurological Diseases and Disorders

Ion channels play a critical role in the nervous system particularly in neurons such as muscle and excitable neuronal tissue. Various types of channels are involved in neurological functions allowing the brain to receive and process information. These channels act as communication pathways allowing ions to move in and out of the cells through the membrane [13,14].

Plethora of studies report on the importance of ion channels in neurological diseases and disorders. Ion channel regulation, dysfunction or mutation in ion channels (channelopathies)or its regulatory proteins within the nervous system cause numerous neurological and/or neuromuscular diseases and disorders among them multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, Huntington’s, epilepsy, pain, depression, anxiety and deafness [13-18]. Hence, neuronal ion channels are considered as potential therapeutic targets to treat neurological diseases and disorders. Currently, ion channels are therapeutically targeted to treat epilepsy and pain.

An estimated 50 million people suffer from epilepsy across the globe with a further 2.4 million diagnosed yearly. A majority of those who suffer from this disorder, 60 percent, have idiopathic epilepsy which has no detectible cause. The remaining suffer from symptomatic epilepsy with a known cause such as a brain damage from prenatal or perinatal injuries including traumatic birth with oxygen loss or low birth weight, a stroke, a brain tumor and certain genetic syndrome [19].

An epileptic seizure takes place when too much electrical signaling occurs in the brain causing uncontrolled, excitatory synaptic transmission. Voltage-Gated Sodium (NaV) ion channels play an essential role in driving the electrical signals in the brain. Therapeutic agents such as phenytoin, carbamazepine and topiramate, which are NaV channel blockers, are used to treat epilepsy [15,20,21]. Also, lignocaine which is a sodium channel blocker is used as local anesthesia [22]. Similarly, gabapentin and ziconotide target the calcium channel (blocker) and are used to treat pain [17,23].

Ion Channels as Drug Target in Diabetes

K_ATP channels are crucial in the regulation of glucose-induced insulin secretion. In pancreatic β-cells, an increase in ATP/ADP ratio, which is generated by glucose uptake and metabolism, closes the K_ATP channels to elicit membrane depolarization, calcium influx and a secretion of insulin, the primary hormone of glucose homeostasis [1]. In the pancreatic β-cell (Figure 1), K_ATP channels are composed of the Kir6.2 pore with the SUR1 regulatory subunit and regulate insulin release. Insulin release is generated by the opening of voltagegated Ca²⁺ channels and Ca²⁺ influx. In hyperglycaemia, an increased transport of glucose occurs into the β-cells resulting in an elevated intracellular ATP, promoting closure of the K_ATP channels and membrane depolarization [1,24]. This K_ATP channel mechanism can be mimicked by sulphonylurea drugs, for example, glibenclamide, which inhibit the K_ATP channel directly in the pancreatic β-cells (Figure 1). The inhibition causes cell membrane depolarization, opening of voltage-dependent calcium channels, thus triggering an increase in intracellular calcium into the β-cell stimulating insulin release [1]. Mutations in K_ATP channels cause physiological dysfunction of this channel leading to pathological consequences such as permanent neonatal diabetes, developmental delay with epilepsy and congenital hyperinsulinism [1,6] (Figure 1).

    

    

    Figure 1: The KATP channel regulation of insulin release in pancreatic β-cells.
When the glucose level increases it causes a rise in the ATP/ADP ratio
and in its turn ATP binds to the KATP channel, which closes the channel.
Depolarization of the membrane then opens the calcium channel which
causes the insulin to release. This drawing illustrates the mimicked pathway
which sulphonylurea drugs by acting to inhibit the KATP channels can
increase insulin secretion, which is used in the treatment of type-2 diabetes.