Paradoxical Potentiation of Neuronal T-Type Ca²⁺Current by ATP at Resting Membrane Potential

Abstract

Despite the marked influence on neuronal physiology of the low-voltage activated T-type Ca 2ϩ currents, little is known about the intracellular pathways and neurotransmitters involved in their regulations. Here, we report that in thalamocortical neurons a phosphorylation mechanism induces an increase both in the current amplitude (1.5 Ϯ 0.27-fold in the ventrobasal nucleus) and its inactivation kinetics. Dialysis of the neuron with an ATP-free solution suppresses the T-current potentiation, whereas it becomes irreversible in the presence of ATP␥S. Phosphorylation occurs when the channels are inactivated and is slowly removed when they recover from inactivation and remain in closed states (time constants of the induction and removal of the potentiation: 579 Ϯ 143 msec and 4.9 Ϯ 1.1 sec, respectively, at 25°C). The resulting apparent voltage sensitivity of this regulation follows the voltage dependence of the current steadystate inactivation. Thus, the current is paradoxically inhibited when the preceding hyperpolarization is lengthened, and maximal currents are generated after transient hyperpolarizations with a duration (0.7-1.5 sec) that is defined by the balance between the kinetics of the dephosphorylation and deinactivation. In addition, the phosphorylation will facilitate the generation of T current at resting membrane potential. This potentiation, which is specific to sensory thalamocortical neurons, would markedly influence the electroresponsiveness of these neurons and represent the first evidence of a regulation of native Cav3.1 channels.

Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation

“…Later in the night, the membrane potential of thalamocortical neurons becomes more depolarized and they contribute to spindle generation. Such changes of membrane potential of thalamocortical neurons could occur either as changes in the activities of neuromodulatory systems (Steriade and McCarley 2005) or as an upregulation of h-current (Luthi and McCormick 1999), which eventually leads to a reduction of T-current (Leresche et al 2004) and low-threshold Ca 2ϩ spikes. Therefore, sleep pressure expressed as enhanced slow-wave activity at the beginning of sleep or sleep deprivation might partially be mediated by the thalamus.…”

Cell-Specific Alterations of T-Type Calcium Current in Painful Diabetic Neuropathy Enhance Excitability of Sensory Neurons

“…For example, recombinant ␣1H T-type channels are stimulated by Ca 2ϩ /calmodulin-dependent kinase II (Wolfe et al, 2002). In thalamic native neurons mostly based on ␣1G isoform, ATP causes a paradoxical potentiation of T-type currents at depolarized membrane potentials (Leresche et al, 2004). This can cause more T-type channels to be available for activation at physiological membrane potentials (e.g., Ϫ60 mV), a consequence that is similar to our findings in DRG cells at membrane potentials of Ϫ40 mV.…”

T current potentiation increases the occurrence and temporal fidelity of synaptically evoked burst firing in sensory thalamic neurons

“…Recently, we demonstrated that, in sensory TC neurons, IT amplitude can be transiently potentiated by a phosphorylation mechanism, which exclusively occurs when the channels are inactivated, i.e., after a period of neuronal depolarization (14). Here, we systematically studied in vitro how this IT potentiation affects high-frequency burst output of TC neurons, using both direct current injection and synaptic potentials.…”

“…However, extensive in vitro characterization of the low-voltage activated T-type Ca 2ϩ channels that underlie an LTS (11,12) has clearly indicated that these channels are fully inactivated in the range of membrane potentials believed to be associated with the wake state (13) and require substantial and prolonged hyperpolarization to de-inactivate [800-ms hyperpolarization to Ϫ100 mV to fully recover from inactivation (14)]. Therefore, the mechanisms that allow the expression of a physiologically significant T current (IT) during wakefulness remain controversial (13).…”