RT Journal Article
SR Electronic
T1 Selective T-Type Calcium Channel Block in Thalamic Neurons Reveals Channel Redundancy and Physiological Impact of <em>I</em><sub>Twindow</sub>
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 99
OP 109
DO 10.1523/JNEUROSCI.4305-09.2010
VO 30
IS 1
A1 Fanny M. Dreyfus
A1 Anne Tscherter
A1 Adam C. Errington
A1 John J. Renger
A1 Hee-Sup Shin
A1 Victor N. Uebele
A1 Vincenzo Crunelli
A1 Régis C. Lambert
A1 Nathalie Leresche
YR 2010
UL http://www.jneurosci.org/content/30/1/99.abstract
AB Although it is well established that low-voltage-activated T-type Ca2+ 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 Ca2+ homeostasis. Recently, a novel series of piperidine-based molecules has been shown to selectively block recombinant T-type but not high-voltage-activated (HVA) Ca2+ 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 (IC50 = 22 nm), and reversible inhibition of T-type Ca2+ currents of thalamocortical and reticular thalamic neurons, without any action on HVA Ca2+ currents, Na+ currents, action potentials, and glutamatergic and GABAergic synaptic currents. Thus, under current-clamp conditions, the low-threshold Ca2+ 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 Ca2+ channels in neurons and its contribution to the resting membrane potential of thalamic neurons and to the Up state of their intrinsically generated slow (&lt;1 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.