CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 5, Issue 6, 2006

Voltage-gated calcium (Ca2+) channels are heteromeric complexes found in the plasma membrane of virtually all cell types and show a high level of electrophysiological and pharmacological diversity. On the basis of the membrane potential at which they activate, these channels are subdivided into high voltage-activated (HVA) and low voltage-activated (LVA) or transient (Ttype) Ca2+ channels. These channels in nerve tissue play a central role in controlling cell excitability and neurotransmitter release. Whereas it has been known that HVA-type Ca2+ currents arise from multiple forms of Ca2+ channels with distinct pharmacological properties, the extent to which T-type Ca2+ current arises from multiple Ca2+ channel subtypes became clear more recently. Recent cloning of 1 subunits of T-type channels has revealed the existence of at least three subtypes named G (CaV3.1), H (CaV3.2) and I (CaV3.3) that are likely to contribute to the heterogeneity of T-type Ca2+ currents observed in native cells. Although T-type currents are relatively easy to study in isolation from other Ca2+ current components by virtue of their unique biophysical properties such as activation, inactivation and deactivation, pharmacological tools for identification and investigation of T-type currents are limited. However, recent cloning of T-type calcium channels and development of more selective blockers of T-type channels allowed better understanding of the roles of these channels in control of the variety of physiological functions in the central nervous system (CNS) and peripheral tissues. Thus, the major roles for the T-type channels in neurons include promotion of Ca2+-dependent burst firing, low-amplitude intrinsic neuronal oscillations, promotion of Ca2+ entry and boosting of synaptic signals. Furthermore, T-type currents in the thalamus appear to play a role in seizure susceptibility and initiation and T-type channels in peripheral sensory neurons play an important role in boosting of pain signals. In this review, we summarize the most recent evidence of the multiple roles of T-type calcium channels in neurons and their role in various physiological and pathological conditions such as pain disorders, absence seizure and sleep disorders. Better definition of the pharmacological properties of different T-type current variants in these cells is of major importance in understanding the physiological role of these currents and their participation in the effects of clinical drugs. Furthermore, future functional studies and development of selective blockers of T-type channels will allow better understanding of their role in pathological processes of the central and peripheral nervous system as well.

The presence of T-channels in thalamic cells allows for the generation of rhythmic bursts of spikes and the existence of two firing modes in thalamic cells: tonic and bursting. This intrinsic electrophysiological property has fundamental consequences for the functional properties of the thalamus across waking and sleep stages and is centrally implicated in a growing number of pathological states. Rhythmic bursting brings about highly synchronized activity throughout corticothalamic circuits which is incompatible with the relay of information through the thalamus. Understanding the conditions that determine the change in firing mode of thalamic cells as well as the role of bursting in the generation of synchronized oscillations is critical to understand the function of the thalamus. The functional properties of T-channels and the resulting low threshold spike are discussed here with emphasis on the differences in the bursting properties of reticular thalamic and thalamocortical neurons. The role of thalamic bursting in the generation of sleep oscillations and their specific sequence during slow wave sleep will also be discussed.

Voltage-gated calcium channels are found in the plasma membrane of many excitable and non-excitable cells. When open, they permit influx of calcium, which acts as a second messenger to initiate diverse physiological cellular processes. Ten unique α 1 subunits, grouped in three families (CaV1, CaV2, and CaV3), encode biophysically and pharmacologically distinct low-voltage-activated T-type and high-voltage-activated L-type, N-type, P/Q-type, and R-type calcium channels. T-type calcium channels are found in neurons where they generate low-threshold calcium spikes and influence action potential firing patterns, in heart cells where they influence pacemaking and impulse conduction, in smooth muscle cells where they regulate myogenic tone and proliferation, in endocrine cells where they regulate hormone secretion, and in sperm where they regulate the acrosome reaction. Validation of T-type calcium channels in disease is based on an abundance of data pertaining to clinical efficacy of T-type calcium channel blockers in certain human conditions as well as information relating to the distribution, functional properties, and physiological roles of these channels. This review focuses on the cellular and molecular pharmacology of T-type calcium channels. It describes novel research approaches to discover potent and selective T-type calcium channel modulators as potential drugs for treating human disease and as tools for understanding better the physiological roles of T-type calcium channels.

This review summarizes recent progress on the molecular biology of low voltage-gated, T-type, calcium channels. The genes encoding these channels were identified by molecular cloning of cDNAs that were similar in sequence to the α1 subunit of high voltage-activated Ca2+ channels. Three T-channel genes were identified: CACNA1G, encoding Cav3.1; CACNA1H, encoding Cav3.2; and CACNA1I, encoding Cav3.3. Recent studies have focused on how these genes give rise to alternatively spliced transcripts, and how this splicing affects channel activity. A second area of focus is on how single nucleotide polymorphisms (SNPs) alter channel activity. Based on their distribution in thalamic nuclei, coupled with the physiological role they play in thalamic oscillations, leads to the conclusion that SNPs in T-channel genes may contribute to neurological disorders characterized by thalamocortical dysrhythmia, such as generalized epilepsy.

As T-type calcium channels open near resting membrane potential and markedly influence neuronal excitability their activity needs to be tightly regulated. Few neuronal T-current regulations have been described so far, but interestingly some of them involve unusual mechanisms like G protein-independent but receptor-coupled modulation, while the use of recombinant channels has established both a direct action of Gβγ subunits, anandamide, arachidonic acid and a phophorylation process by CaMKII. Nearly all reported types of modulation involve Cav3.2 channels while no regulation of Cav3.1 has been reported, a difference that may originate from diversities in the intracellular loop connecting the II and III domains of the two isotypes. The search for T-current regulators requires taking into account their peculiar activation properties, since a close link may exist between the channel conformation and its modulation. Indeed, in thalamocortical neurons a phosphorylationmediated regulation of the amplitude of the T-current has been shown to be highly dependent upon the state of the channel and only to become apparent when the channels are in the voltage range close to neuronal resting membrane potential.

Thalamocortical neurons in mammals fire action potentials in two different modes, burst or tonic, depending on the cellular state. The burst firing is driven by the low threshold Ca2+ spike that is generated by Ca2+ influx through T-type Ca2+ channels, and has long been implicated in the pathogenesis of absence epilepsy and the regulation of sleep rhythms. The recent availability of the knock-out mice for theα1G locus, encoding the predominant form of T-type channels in thalamocortical neurons, has provided an opportunity to examine those ideas at the level of organism. In this review we will describe recent results demonstrating the essential role of thalamic bursts in certain forms of absence seizures and in some of the sleep rhythms. Available information so far reveals the sensory gating role of thalamic bursts, and thus of 1G T-type channels. Understanding of the molecular targets involved in pathophysiological mechanisms will help develop drugs to control those pathological states.

It is well established that the voltage-gated calcium (Ca2+) channels can modulate neuronal activity in the peripheral and central nervous system causing a variety of behavioral and neuro-endocrine changes in humans and animals. While much attention was focused on the modulation of high voltage-activated (HVA)-type Ca2+ channels, the role of low voltage-activated (LVA) or transient (T) type Ca2+ channels in sensory processing, and in particular pain processing (nociception) is much less certain. However, recent evidence strongly suggests that modulation of both central and peripheral T-type Ca2+ channels influences somatic and visceral nociceptive inputs and that modulation of T-type Ca2+ currents results in significant alteration of pain threshold in a variety of animal pain models. Therefore, T-type Ca2+ channels in peripheral and central neurons, although previously unrecognized, may be important targets for analgesic therapeutic agents including endogenous compounds. Currently available pain therapies remain insufficient with limited efficacy and numerous side effects. Hence, studies of selective and potent modulators of neuronal T-type Ca2+ channels may greatly aid in revealing roles for these channels in sensory pathways (nociception in particular) and in the development of novel and potentially more effective and safer pain therapies. In the present review, we summarize the putative role of peripheral and central T-type Ca2+ channels in nociception and our recent in vivo and in vitro studies focusing primarily on 5α- and 5β- reduced neuroactive steroids and redox agents that are potent modulators of neuronal T-type Ca2+ channels.

The electroresponsiveness fingerprint of a neuron reflects the types and distributions of the ionic channels that are embedded in the neuronal membrane as well as its morphology. Theoretical analysis shows that subtle changes in the density of channels can contribute substantially to the electroresponsive fingerprints of neurons. We have confirmed these predictions, using the dynamic clamp approach to emulate changes in channels' densities in neurons from the inferior olive. We demonstrate how the density of T-type channels determines the behavioral destiny of neurons. We argue that regulation of channel densities could be an efficient mechanism for controlling the electrical activity of single cells, as well as the output of neuronal networks.