Potassium Channels
Potassium channels play a major role in regulating neuronal excitability. Although more than 20 types of potassium channels have been identified by biophysical studies, there are four major groups: calcium-activated, voltage-gated, sodium-activated, and inwardly rectifying potassium channels. These different types of potassium channels are regulated by neuromodulators, ions, and second messenger systems. The opening of potassium channels has the effect of hyperpolarizing neurons or reversing depolarizing actions that exist during the transmission of the action potential or the neuroexcit-atory input. Following depolarization, several calcium-activated potassium channels play a major role in the after-hyperpolarization that occurs to restore the resting potential of a neuron (39). Electrographic studies on hip-pocampal neurons from patients undergoing temporal lobectomies have demonstrated alterations in potassium channels in epileptic tissue (40). In addition, compounds that can block potassium channels and prevent the effect of these channels on hyperpolarization are potent convul-sants. Fluoraminopyridine and dendrotoxin-I are potent convulsants that have been used in numerous animal models to cause seizures (41, 42). In addition, compounds that are currently used as antihypertensive drugs, including chromakalim, minoxidil, diazoxide, and penicidil, act as potassium channel openers in muscle membranes and may have potential for use as anticonvulsant compounds (43, 44). The possibility of developing new classes of compounds that can activate or potentiate potassium channel activity may play an important role in increasing hyperpolarization following excessive excitatory activity and may serve to reverse the decreased levels of some potassium channels observed in patients with epilepsy.
Some anticonvulsant compounds may also play a role as potassium channel openers. Carbamazepine has been found to enhance potassium conductances in neurons (45). Other potential anticonvulsant compounds are being evaluated that may also potentiate potassium channel activation. Investigation of anticonvulsant drugs regulating potassium channels is a major frontier in the development of new anticonvulsant compounds. The small conductance Ca2+-activated K+ (SK) channels inhibit epi-leptiform bursting in hippocampal CA3 neurons. Compounds activating or inhibiting voltage-gated potassium channels formed by KCNQ2, KCNQ3, and KCNQ5 assembly (M-channels) are undergoing clinical trials for epilepsy, stroke, and Alzheimer's disease (46). Mutation in KCNQ2/3 causing mild reduction of M-channel activity is thought to enhance neuronal excitability associated with benign neonatal seizures. On the other hand, M-channel openers decrease the hyperexcitability responsible for epileptic seizures and migraine. Indeed, retigabine is thought to produce antiepileptic effect by opening the KNCQ2/3 channels (47, 48). This is a promising area for novel anticonvulsant drug development.
It is only in the recent past that scientists have begun to decipher the role of the hyperpolarization-activated cation (HCN) channel or h-channel (Ih) in regulating neuronal excitability and modulating seizures. The HCN family of genes consists of four subtypes and encodes HCN or Ih (49). HCN1 and HCN2 are the most prevalent subtypes in cortex and hippocampus, and HCN2 and HCN4 predominate in the thalamus. HCN3 is modestly expressed in brain (50). HCN has the unique capacity of being able to produce opposite biophysical effects. Thus, it can be either excitatory or inhibitory with respect to its influence on action potential firing. For example, Ih can diminish the effect of excitatory inputs, or it can set normal resting membrane potential, depolarizing the membrane from the K+ reversal potential toward the firing threshold, thereby producing an excitatory effect (51). There is a growing body of evidence implicating HCN in epileptogenesis (51-54). For example, Ih- and GABA-mediated inhibition is increased in febrile seizures (55, 56). Moreover, genetic deletion of HCN2 resulted in a mouse phenotype that exhibited spontaneous absence seizures as well as cardiac sinus arrhythmias, indicating that the absence of HCN2 is proconvulsive (57). There is conflicting pharmacologic evidence for the role of HCN in epilepsy (51). Certain AEDs, such as lamotrigine, act beyond their normal target—the Na+ channels—and upregulate Ih, and they reduce action potential firing that is initiated from dendritic depolarization but not from somatic depolarization (52). On the other hand, other Na+ channel blockers, such as carbamazepine or phenytoin, did not lower dendritic excitability (52). Thus, the action of lamotrigine on HCN may constitute an important, novel anticonvulsant mechanism. The role of the HCN channel in epilepsy is an important area for further investigation.
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