Specific contribution of human T-type calcium channel isotypes (α1G α1H and α1I) to neuronal excitability

摘要

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 α1G (CaV3.1), α1H (CaV3.2) and α1I (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 α1G channels and, to a lesser extent, α1H channels produced large and transient currents, while currents related to α1I 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 α1I currents contributed to sustained electrical activities, while α1G and α1H currents generated short burst firing. Modelling experiments with the NEURON model further revealed that the α1G channel and α1I 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 α1I 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.