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Specific contribution of human T-type calcium channel isotypes (_1G, _1H and _1I) to neuronal excitability

Jean Chemin, Arnaud Monteil, Edward Perez-Reyes *, Emmanuel Bourinet, Joël Nargeot and Philippe Lory

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 (Ca_V3.1), _1H (Ca_V3.2) and _1I (Ca_V3.3) 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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