Voltage Gated Calcium Channels

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Voltage-regulated or gated calcium channels affect neuronal excitability. As an action potential arrives at a nerve terminal, depolarization of the nerve terminal membrane causes entry of calcium through voltage-gated calcium channels with subsequent release of neurotransmitters. This is the classic paradigm for calcium-mediated neu-rotransmitter release and was the initial observation that demonstrated the importance of calcium in neuronal excitability, but little was understood about the specific mechanisms of calcium channels in brain.

Early insight into the neuropharmacology of calcium channels came from studies of smooth muscle and cardiac cells during the 1970s. The dihydropyridine type of calcium channel blocker and related molecules were shown to be effective in blocking calcium channels in peripheral tissue (112, 116, 117). These compounds were classified as "organic calcium channel blockers'' and represented a major advance in pharmacology. Numerous analogues were developed, and specific binding sites for the dihydropyridines and other analogs were identified and characterized. This led to the first molecular characterization of calcium channels and their regulation by specific receptor sites. A major controversy developed based on the observation that the organic calcium blockers, effective in inhibiting calcium entry into non-neuronal tissue, seemed to be ineffective in blocking voltage-gated calcium entry into neurons (118). Numerous investigators demonstrated that calcium entry as a result of neuronal activity was not significantly inhibited by therapeutic or relevant concentrations of the organic calcium channel blockers (112). Because there was at that time no clear evidence for more than one type of calcium channel, this dichotomy was not well understood and was attributed to unusual properties of the neuronal membrane and to specific differences in drug penetration into the nervous system. More recent studies using benzodiazepines and phenothiazines (119-122) demonstrated that these compounds in fact could significantly block voltage-gated calcium channels in neurons. These results indicated that calcium channels in brain were distinct from calcium channels in peripheral tissue.

With the development of patch and voltage clamp technology, more sophisticated characterization of calcium channels has been possible. It is now clear that there are at least three, and possibly more, types of calcium channels in neurons (118, 123, 124). One type of voltage-gated calcium channel is insensitive to dihydropyridines, while a second type of calcium channel is sensitive to these compounds. A third type of brain membrane calcium channel has also been postulated that is different from the first two types of channels. Although a set terminology has not been developed for these different channels, initial classification by Tsien (124) is currently in use and describes these channels as the T-, N-, and L-type channels, respectively.

The heterogeneity of calcium channels provides a major insight into different mechanisms of regulating calcium excitability in the nervous system. These observations also explain the fact that the major voltage-gated calcium channels in brain that were insensitive to dihydropyridines were a different class of channel from those found in peripheral tissues. In certain regions of the nervous system and at certain sites on the cell body, however, there are calcium channels that are sensitive to dihydropyridines and are similar to those calcium channels in non-neuronal tissue. The different types of calcium channels are distributed in characteristic patterns over the surface of a neuron. Some channels may be localized at the synapse, while others may be present at a higher density at the cell body. The heterogeneity and individual functions of specific types of calcium channels are important areas for further investigation, such as the development of specific drugs to regulate each type of channel.

Several anticonvulsant compounds block or alter calcium entry through voltage-gated calcium channels. Ferrendelli and coworkers (125, 126) described the ability of phenytoin, phenobarbital, carbamazepine, but not ethosuximide, to block voltage-dependent calcium entry into isolated nerve terminal preparations. Subsequent studies have demonstrated that benzodiazepines, as well as phenytoin and barbiturates, can regulate calcium entry into isolated neurons. However, the concentrations of antiepileptic drugs that are required to block calcium entry are in the low micromolar range, concentrations that are approximately one order of magnitude higher than the therapeutic levels of these drugs achieved in spinal fluid. Although these concentrations may be relevant to anticonvulsant actions, they are more likely related to toxic side effects.

Thalamic relay neurons fire in two different modes: burst and tonic. T-type Ca2+ channels underlie the burst firings. When activated, T-type channels produce low-threshold Ca2+ currents that lead to the generation of a burst of action potentials (127). Burst firing of thalamic neurons have been implicated to play an important role in the pathogenesis of absence epilepsy (128). Ethosuximide, a known antiepileptic drug, is known to block T-type Ca2+ channels in thalamic relay neurons (129). Analysis of knockout mouse for the alpha1G gene coding for a subtype of T-type Ca2+ channels demonstrated absence of low-threshold, T-type, Ca2+ currents and an inability to induce burst firing in the thalamic relay neurons (130, 131). Alpha1G knockout mice were resistant to GABAb receptor agonists; baclofen and gamma-hydrobutyrate (GHB) induced seizures (132). T-type Ca2+ channels represent a novel pharmacologic target for development of drugs for the treatment of epilepsy.

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