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Received September 19, 2001
Accepted after revision January 16, 2002
1 Institut de Génétique Humaine, CNRS UPR 1142, 141 rue de la Cardonille, F-34396 Montpellier cedex 05, France
2 Department of Pharmacology, University of Virgina, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
3 Institut de Génétique Humaine (IGH), CNRS UPR 1142, 141, rue de la Cardonille, F-34396 Montpellier cedex 05, France
* To whom correspondence should be addressed. E-mail: philippe.lory{at}igh.cnrs.fr.
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 
1G (CaV3.1), 1H (CaV3.2) and 1I (CaV3.3) 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 1G channels and, to a lesser extent, 1H channels produced large and transient currents, while currents related to 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 1I currents contributed to sustained electrical activities, while 1G and 1H currents generated short burst firing. Modelling experiments with the NEURON model further revealed that the 1G channel and 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 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.
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