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The K v family has more than 40 members that are classified into 12 distinct subfamilies based on their amino acid sequence homology K v 1 to K v 12 [ 37 ]. K v channels are valid molecular targets for both convulsant and anticonvulsant agents. These inhibitory actions enhance excitability and unlikely contribute to anticonvulsant activity.


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CICs are expressed in the hippocampus where they mediate chloride currents in pyramidal cells of the hippocampus. They are involved in regulating chloride homeostasis [ 43 ], excitability [ 44 ], and acidification of synaptic vesicles [ 45 ].

Modulation of T-type Ca2+ channels by Lavender and Rosemary extracts

However, functional studies in transfected cells suggest that the mutations cause a loss of function [ 50 ]. HCN channel topology consisting of six transmembrane domains S1—S6. S4, the putative voltage sensor characterized by the presence of 11 basic amino acids two lysines, seven arginines, and two histidines within its domain, is present in all the four HCN subunits.

Genes coding for four distinct channel isoforms have been cloned HCN1—4 , and HCN channel transcripts and proteins are widely and variably distributed throughout the mammalian central nervous system [ 56 ]. Each of the four identified subunits HCN1—4 has six transmembrane segments. HCN2 is generally considered to be widely distributed in the nervous system, and HCN3 is generally poorly expressed except for the olfactory bulb, hypothalamus and retinal cones pedicles [ 53 ].

HCN1 has been detected specifically in the neocortex, hippocampus, cerebellar cortex, and brainstem [ 56 ], whereas HCN4 channels are highly expressed in particular in thalamic nuclei, basal ganglia, and olfactory bulb [ 56 ]. At the cellular level, several basic functions including control of the membrane resting potential and dendritic integration have been attributed to these channels. Dysregulation of HCN channel expression and aberrant HCN channel function have been implicated in various types of idiopathic and acquired epilepsies.

HCN2 deficiencies are pathological hallmarks of absence epilepsy [ 58 ]. Genetic studies suggest that the suppression of HCN channels in neurons is involved in generation of neuronal hyperexcitability, which have been reported in temporal lobe epilepsy, the most common and severe form of epilepsy in adults [ 60 ]. I h is an attractive potential AED target for different types of epilepsy. However, the complexity and diversity of the mechanisms connecting impaired HCN channel activity with epilepsy make it very challenging to develop a generally applicable rationale for the design of anticonvulsant drugs based on HCN channels.

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Drugs targeting HCN1 might be relevant for limbic seizures, whereas those affecting HCN2 may be more relevant to absence epilepsy. Lamotrigine and gabapentin upregulate the activity of HCN channels [ 62 , 63 ]. It may be speculated that the action of both drugs is directed primarily at HCN1, which is the main HCN subtype in the cortex and hippocampus. In rat hippocampal pyramidal neurons, lamotrigine has also been reported to decrease dendritic excitability by increasing I h [ 64 ]. The subunit composition determines the biophysical properties, pharmacological characteristics [most notably the sensitivity to benzodiazepines BZ ], and subcellular localization of the GABA A receptors [ 67 ].

Their modulatory domains include binding sites for benzodiazepines BZ site , GABA, barbiturates, nonbarbiturate anesthetics and ethanol, neurosteroids, picrotoxin, penicillin, and zinc. Genetic studies in humans reveal a range of idiopathic generalized epilepsy syndromes linked to mutations in the GABA A receptor [ 69 ]. GABA A receptors are acknowledged targets of many available anticonvulsants including drugs enhancing GABA A receptor action through a direct interaction with the receptor benzodiazepines, barbiturates, propofol, stiripentol, topiramate, carbamazepine, phenytoin, felbamate or indirectly by increasing the available GABA tiagabine, vigabatrine, gabapentin, valproate [ 68 ].

Furthermore, anticonvulsants can reduce the depolarizing effects of GABA A receptors by inhibiting carbonic anhydrase topiramate, zonisamide, acetazolamide [ 68 ]. Studies in genetically modified mice have helped establish the role played by subunit composition in the antiepileptic and other pharmacological actions of drugs acting on the GABA A receptor [ 72 ]. Nonbenzodiazepines that bind to the benzodiazepine site have been developed; some are partial agonists with reduced efficacy. They are tetrameric structures with four subunits for the AMPA receptors, five subunits for the kainite receptors and seven subunits for the NMDA receptors [ 75 ].

Little evidence for spontaneous mutations involving glutamate receptors has been demonstrated in epilepsy syndromes in human or mouse. Substantial effort has been devoted toward the development of ionotropic glutamate receptor antagonists for epilepsy therapy because of the role of glutamate in the pathophysiology of seizures and the empirical evidence that these antagonists are protective in various animal seizure models [ 77 ].

Competitive and noncompetitive NMDA receptor antagonists demonstrated the ability to block seizures in rodent epilepsy and possess protective activity in some rodent models [ 78 , 79 ]. Competitive NMDA antagonists appeared the most promising in models of generalized seizures.

AMPA receptor antagonists, which are anticonvulsant in a broad range of rodent animal models, have been identified and may have greater potential clinical utility than do the NMDA antagonists [ 15 ]. Three marketed AEDs have been shown to interact with glutamate receptors. Phenobarbital decreases the depolarizing or excitotoxic action of AMPA and kainate at concentrations similar to those at which it potentiates GABA [ 80 ]. Felbamate has several different pharmacological actions including specific inhibitory effect on NMDA receptors that have been proposed as contributing to its clinical efficacy [ 83 ].

Increase in extracellular proton concentrations, which is associated with physiological conditions such as synaptic signaling and pathological conditions such as tissue inflammation, ischemic stroke, traumatic brain injury, and epileptic seizure, activates this unique family of membrane ion channels.

The ASICs rapidly respond to a reduction in extracellular pH with an inward cation current that is quickly inactivated despite the continuous presence of protons in the medium. ASICs are involved in nociception in sensory neurons when injury or inflammation causes acidification.

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Calcium and Ion Channel Modulation

The inhibition of ASICs might therefore reduce excitatory synaptic neurotransmission resulting to anticonvulsant actions [ 4 ]. ASIC antagonists might minimize these adverse consequences of seizures. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. A channel modulator , or ion channel modulator , is a type of drug which modulates ion channels. They include channel blockers and channel openers.

Ion channels are typically categorised by gating mechanism and by the ion they conduct. Note that an ion channel may overlap between different categories. Some channels conduct multiple ion currents and some are gated by multiple mechanisms. Voltage gated ion channels. Ligand gated ion channels. Ion channels gated by other mechanisms e. These types of channels can also be pharmacologically modulated. For lists of the substances that pharmacologically modulate them, see their respective articles. Ion channels can also be modulated indirectly.

Ion channels can also be modulated by reuptake inhibitors and releasing agents. From Wikipedia, the free encyclopedia. Drug Discovery Today. See Ion channel modulators.

042 How Calcium ion release results in Muscle Contraction

Histamine receptor agonist Histamine receptor antagonist H 1 H 2 H 3. Opioid modulator Opioid receptor agonist Opioid receptor antagonist Enkephalinase inhibitor. Cofactor see Enzyme cofactors Precursor see Amino acids.


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