Specific contribution of human T‐type calcium channel isotypes (α_1G, α_1H and α_1I) to neuronal excitability

Abstract

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 a 1G (Ca V 3.1), a 1H (Ca V 3.2) and a 1I (Ca V 3.3) 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 a 1G channels and, to a lesser extent, a 1H channels produced large and transient currents, while currents related to a 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 a 1I currents contributed to sustained electrical activities, while a 1G and a 1H currents generated short burst firing. Modelling experiments with the NEURON model further revealed that the a 1G channel and a 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 a 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.

Enhancement of Excitatory Synaptic Integration by GABAergic Inhibition in the Subthalamic Nucleus

“…Together, our observations and the known biophysical properties of Ca v 3 channels in STN and other neurons indicate that Ca v 3 channels do not participate in the integration of single IPSPs in STN neurons. The increase in the frequency of autonomous activity that was obtained with Ni 2ϩ application in five of six STN neurons supports the existence of Ca v 3 channel-mediated Ca 2ϩ influx during autonomous firing (Williams et al, 1997;Chemin et al, 2002). The increase in firing frequency that accompanies the blockade of an inward Ca 2ϩ current may indicate that Ca v 3 channels are functionally coupled to small and/or large conductance Ca 2ϩ -activated potassium channels (cf.…”

Molecular Identity and Functional Properties of a Novel T-Type Ca2+ Channel Cloned From the Sensory Epithelia of the Mouse Inner Ear

“…As in many other cases, the highest sequence similarities appear at the transmembrane domains and the pore-forming regions (ϳ98%), whereas the lowest was at the intracellular N-and C-termini (ϳ84%). The functional impact of alternative splicing on the property of other isoforms of Ca v 3.1 channels has been reported previously (Chemin et al 2002a). Thus we examined the properties of the newly identified Ca v 3.1 channels in the inner ear.…”

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

“…These differences suggest that the three channels play distinct roles in determining neuronal firing patterns and signal integration. Ca v 3.1 and Ca v 3.2 channels are likely involved in short burst firing as seen in thalamacortical neurons, whereas Ca v 3.3 channels are likely involved in sustained burst firing as seen in thalamic reticular neurons (70).…”