T-type calcium channels: The never ending story (original) (raw)
Related papers
Amazing T-type calcium channels: updating functional properties in health and disease
Pflügers Archiv - European Journal of Physiology, 2014
T-type Ca 2+ channels have gained 15 years after cloning an immense interest as novel players in very unexpected cell functions and many relations to diseases have been discovered. This Special Issue provides a state of the art overview on novel functional properties of T-type Ca 2+ channels, unexpected cellular functions and most importantly will also summarizes and review the involvement of this "tiny, transient" type of Ca 2+ channels in several disease. It is tried to bridge the gap between molecular biophysical properties of T-type Ca 2+ channels and diseases providing finally a translational view on this amazing ion channel.
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.
Low-voltage-activated T-type Ca2+ channels
Although progress in our understanding of T channels and their physiological role has been slower than with other Ca2+ channels, it was clear during this two-day workshop that interest and research in the field remain very intense. Advances have been hampered by many factors: small current amplitude, lack of pharmacological tools, apparent heterogeneity, and lack of a cloned channel. Nevertheless, many interesting roles for T channels have been described, which point to a generally subtle modulatory action. Furthermore, recent results suggest that the above barriers might soon be abolished: new pharmacological tools (mibefradil and newer generation compounds) with T-channel selectivity are being developed and many groups claim to be close to cloning a T channel
WIREs Membr Transp Signal , 2012
T-type channels are unique among the voltage-gated calcium channels in their fast kinetics and low voltages of activation and inactivation, the latter two features allowing them to operate at voltages near the resting membrane potential of most neurons. T-type channels can therefore be recruited by subthreshold depolarizations, and hyperpolarizations that remove inactivation. As such, T-type channels can significantly influence how and when cells reach action potential threshold, and thus are critical regulators of excitability. T-type channels are also significantly conserved within the animal kingdom, present even in animals lacking muscles and nerves, suggesting that they evolved before or very early on during the emergence of neuronal and neuromuscular synapses. Physiologically, T-type channels are involved in multiple processes, and their contributions range from purely electrogenic roles to the activation of calcium-sensitive ion channels, signaling pathways, and other macromolecular complexes. Unfortunately, it has been difficult to prove sufficiency and necessity of T-type channels in many of these processes, in part due to inconsistencies in their suspected contributions. Furthermore, gene knockout studies have failed to show that T-type channels are essential for development or survival, as knockout animals exhibit only weak phenotypes. T-type channels roles are likely dependent on cellular context, and the three mammalian isotypes are expected to be somewhat redundant in their functionality, but have evolved from the single ancestral precursor gene in invertebrates to carry out unique functions, as evidenced by their divergent biophysical properties and protein–protein interaction motifs present within cytoplasmic regions.
Activity-dependent regulation of T-type calcium channels by submembrane calcium ions
Voltage-gated Ca2+ channels are involved in numerous physiological functions and various mechanisms finely tune their activity, including the Ca2+ ion itself. This is well exemplified by the Ca2+-dependent inactivation of L-type Ca2+ channels, whose alteration contributes to the dramatic disease Timothy Syndrome. For T-type Ca2+ channels, a long-held view is that they are not regulated by intracellular Ca2+. Here we challenge this notion by using dedicated electrophysiological protocols on both native and expressed T-type Ca2+ channels. We demonstrate that a rise in submembrane Ca2+ induces a large decrease in T-type current amplitude due to a hyperpolarizing shift in the steady-state inactivation. Activation of most representative Ca2+-permeable ionotropic receptors similarly regulate T-type current properties. Altogether, our data clearly establish that Ca2+ entry exerts a feedback control on T-type channel activity, by modulating the channel availability, a mechanism that critically links cellular properties of T-type Ca2+ channels to their physiological roles.
The many faces of T-type calcium channels
Pflügers Archiv - European Journal of Physiology, 2014
Since the discovery of low-voltage activated T-type calcium channels in sensory neurons and the initial characterization of their physiological function mainly in inferior olive and thalamic neurons, studies on neuronal T-type currents have predominantly focused on the generation of low-threshold spike (and associated action potential burst firing) which is strictly conditioned by a preceding hyperpolarization. This Ttype current mediated activity has become an archetype of the function of these channels, constraining our view of the potential physiological and pathological roles that they may play in controlling the excitability of single cells and neural networks. However, greatly helped by the recent availability of the first potent and selective antagonists for this class of calcium channels, novel T-type current functions are rapidly being uncovered, including their surprising involvement in neuronal excitability at depolarized membrane potentials and their complex control of dendritic integration and neurotransmitter release. These and other data summarized in this short review clearly indicate a much wider physiological involvement of T-type channels in neuronal activity than previously expected.
Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Low voltage-activated Ca2+ channels play important roles in pacing neuronal firing and producing network oscillations, such as those that occur during sleep and epilepsy. Here we describe the cloning and expression of the third member of the T-type family, alpha1I or CavT.3, from rat brain. Northern analysis indicated that it is predominantly expressed in brain. Expression of the cloned channel in either Xenopus oocytes or stably transfected human embryonic kidney-293 cells revealed novel gating properties. We compared these electrophysiological properties to those of the cloned T-type channels alpha1G and alpha1H and to the high voltage-activated channels formed by alpha1Ebeta3. The alpha1I channels opened after small depolarizations of the membrane similar to alpha1G and alpha1H but at more depolarized potentials. The kinetics of activation and inactivation were dramatically slower, which allows the channel to act as a Ca2+ injector. In oocytes, the kinetics were even slower, sugg...
Molecular characterization of a novel family of low voltage-activated, T-type, calcium channels
Journal of bioenergetics and biomembranes, 1998
Low voltage-activated, T-type, calcium channels are thought to be involved in pacemaker activity, low threshold Ca2+ spikes, neuronal oscillations and resonance, and rebound burst firing. Mutations in T-type channel genes may be a contributing factor to neurological and cardiovascular disorders, such as epilepsy, arrhythmia, and hypertension. Due to the lack of selective blockers, little is known about their structure or molecular biology. This review discusses our recent findings on the cloning, chromosomal localization, and functional expression, of two novel channels, alpha1G and alpha1H. The biophysical properties of these cloned channels (distinctive voltage dependence, kinetics, and single channel conductance) demonstrates that these channels are members of the T-type Ca2+ channel family.