Selective T-Type Calcium Channel Block in Thalamic Neurons Reveals Channel Redundancy and Physiological Impact of ITwindow

摘要: Although it is well established that low-voltage-activated T-type Ca(2+) channels play a key role in many neurophysiological functions and pathological states, the lack of selective potent antagonists has so far hampered detailed analysis full impact these might have on single-cell neuronal network excitability as homeostasis. Recently, novel series piperidine-based molecules been shown to selectively block recombinant but not high-voltage-activated (HVA) affect number physiological channel-dependent behaviors. Here we directly show one compounds, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), exerts specific, (IC(50) = 22 nm), reversible inhibition currents thalamocortical reticular thalamic neurons, without any action HVA currents, Na(+) potentials, glutamatergic GABAergic synaptic currents. Thus, under current-clamp conditions, low-threshold potential (LTCP)-dependent high-frequency burst firing neurons abolished by TTA-P2, whereas tonic remains unaltered. Using provide first direct demonstration presence window component its contribution resting membrane Up state their intrinsically generated slow (<1 Hz) oscillation. Moreover, demonstrate activation only small fraction channel population required generate robust LTCPs, suggesting LTCP-driven bursts potentials can be evoked at depolarized where vast majority are inactivated.