The many faces of T-type calcium channels (original) (raw)
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Modulation of Neuronal T-Type Calcium Channels
CNS & Neurological Disorders - Drug Targets, 2006
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 G 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.
T-type Ca2+ channels as therapeutic targets in the nervous system
Current Opinion in Pharmacology, 2008
Low-voltage-activated calcium channels, also known as T-type calcium channels, are widely expressed in various types of neurons. In contrast to high-voltage-activated calcium channels which can be activated by a strong depolarization of membrane potential, T-type channels can be activated by a weak depolarization near the resting membrane potential once deinactivated by hyperpolarization, and therefore can regulate the excitability and electroresponsiveness of neurons under physiological conditions near resting states. Recently, the molecular diversity and functional multiplicity of T-type channels have been demonstrated through molecular genetic studies coupled with physiological and behavioral analysis. Understanding the functional consequences of modulation of each subtype of these channels in vivo could point to the right direction for developing therapeutic tools for relevant diseases.
Physiology and Pathology of Voltage- Gated T-Type Calcium Channels
T-type channels are low voltage-activated members of the calcium channel family that also includes the high voltage-activated Cav1 and Cav2 channels. T-type channels open with only minimal depolarization or in response to hyperpolarization of the cell membrane and are associated with regulating excitability and pacemaking at subthreshold voltages. Interestingly, increasing evidence suggests that the subthreshold properties of T-type channels are exploited for other cellular processes including low-threshold synaptic vesicle release (excitation-secretion coupling), myocyte contraction and tone (excitationcontraction coupling), and cell cycle control. T-type channels are implicated in several pathologies including epilepsy, autism, sleep disturbances, pain, hypertension, and cancer. With the advent of novel blockers selective for T-type channels, their important contributions to normal cellular/organismal physiology, as well as to pathology, are becoming clearer.
The Journal of Neuroscience, 2010
Although it is well established that low-voltage-activated T-type Ca 2ϩ channels play a key role in many neurophysiological functions and pathological states, the lack of selective and potent antagonists has so far hampered a detailed analysis of the full impact these channels might have on single-cell and neuronal network excitability as well as on Ca 2ϩ homeostasis. Recently, a novel series of piperidine-based molecules has been shown to selectively block recombinant T-type but not high-voltage-activated (HVA) Ca 2ϩ channels and to affect a number of physiological and pathological T-type channel-dependent behaviors. Here we directly show that one of these compounds, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), exerts a specific, potent (IC 50 ϭ 22 nM), and reversible inhibition of T-type Ca 2ϩ currents of thalamocortical and reticular thalamic neurons, without any action on HVA Ca 2ϩ currents, Na ϩ currents, action potentials, and glutamatergic and GABAergic synaptic currents. Thus, under current-clamp conditions, the low-threshold Ca 2ϩ potential (LTCP)-dependent high-frequency burst firing of thalamic neurons is abolished by TTA-P2, whereas tonic firing remains unaltered. Using TTA-P2, we provide the first direct demonstration of the presence of a window component of Ca 2ϩ channels in neurons and its contribution to the resting membrane potential of thalamic neurons and to the Up state of their intrinsically generated slow (Ͻ1 Hz) oscillation. Moreover, we demonstrate that activation of only a small fraction of the T-type channel population is required to generate robust LTCPs, suggesting that LTCP-driven bursts of action potentials can be evoked at depolarized potentials where the vast majority of T-type channels are inactivated.
Neuronal T–type calcium channels: What's new? Iftinca: T–type channel regulation
Journal of medicine and life
This review summarizes recent advances in our understanding of neuronal T-type calcium channel regulation as well as their physiological and pathophysiological roles. Through their ability to conduct calcium across the cellular membrane at potentials close to the resting potential, T-type calcium channels are critically important for regulating neuronal excitability, both in the central and peripheral nervous system. T-type channels are also linked to an increasing number of neurological disorders such as the absence epilepsy and neuropathic pain. Although there is substantial literature dealing with regulation of native T-type channels, the underlying molecular mechanism has only recently been addressed. It is, therefore, critical to understand the cellular mechanisms that control T-type channel activity and expression, because this could provide important insight into designing novel therapeutic strategies targeting these channels.
Journal of Physiology-london, 2002
In several types of neurons, firing is an intrinsic property produced by specific classes of ion channels. Low-voltage-activated T-type calcium channels (T-channels), which activate with small membrane depolarizations, can generate burst firing and pacemaker activity. Here we have investigated the specific contribution to neuronal excitability of cloned human T-channel subunits. Using HEK-293 cells transiently transfected with the human a 1G (Ca V 3.1), a 1H (Ca V 3.2) and a 1I (Ca V 3.3) subunits, we describe significant differences among these isotypes in their biophysical properties, which are highlighted in action potential clamp studies. Firing activities occurring in cerebellar Purkinje neurons and in thalamocortical relay neurons used as voltage clamp waveforms revealed that a 1G channels and, to a lesser extent, a 1H channels produced large and transient currents, while currents related to a 1I channels exhibited facilitation and produced a sustained calcium entry associated with the depolarizing after-potential interval. Using simulations of reticular and relay thalamic neuron activities, we show that a 1I currents contributed to sustained electrical activities, while a 1G and a 1H currents generated short burst firing. Modelling experiments with the NEURON model further revealed that the a 1G channel and a 1I channel parameters best accounted for T-channel activities described in thalamocortical relay neurons and in reticular neurons, respectively. Altogether, the data provide evidence for a role of a 1I channel in pacemaker activity and further demonstrate that each T-channel pore-forming subunit displays specific gating properties that account for its unique contribution to neuronal firing.
Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics
The Journal of Physiology, 2011
Non-technical summary Voltage-dependant calcium channels constitute a heterogeneous group playing ubiquitous roles in excitable cells. Among them the low-voltage activated T-type channels generate a family of currents that differ in their biophysical properties reflecting structural or neuromodulatory diversity. These T-type calcium channels are highly expressed in neurons located in the thalamus, a brain structure considered as the gateway to the cortex. Thalamic T-type calcium channels are critically involved in oscillatory neuronal activities associated with sleep or epilepsy and may contribute to sensory processing. Using injections of computer-simulated T-type conductances (a real time mimicry of ionic currents) in biological thalamic neurons, we dissect how the diversity in T-type currents impact on the output of thalamic neurons. We show that very subtle modifications in the properties of the T current that were overlooked so far affect drastically the physiological output of the thalamic neurons and therefore condition the dynamics of thalamo-cortical information integration.
Molecular characterization of a neuronal low-voltage-activated T-type calcium channel
Nature, 1998
The molecular diversity of voltage-activated calcium channels was established by studies showing that channels could be distinguished by their voltage-dependence, deactivation and single-channel conductance. Low-voltage-activated channels are called 'T' type because their currents are both transient (owing to fast inactivation) and tiny (owing to small conductance). T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Here we report the identification of a neuronal T-type channel. Our cloning strategy began with an analysis of Genbank sequences defined as sharing homology with calcium channels. We sequenced an expressed sequence tag (EST), then used it to clone a full-length complementary DNA from rat brain. Northern blot analysis indicated that this gene is expressed predominantly in brain, in particular the amygdala, cerebellum and thalamus. We mapped the human gene ...