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The Journal of Neuroscience, June 16, 2004, 24(24):5592-5602; doi:10.1523/JNEUROSCI.1038-04.2004

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

Nathalie Leresche,¹ Julien Hering,² and Régis C. Lambert²

¹Neurobiologie des Processus Adaptatifs, Unité Mixte de Recherche (UMR) 7102 Centre National de la Recherche Scientifique (CNRS), Université Paris 6, 75252 Paris Cedex 05, France, and ²Laboratoire de Neurobiologie Cellulaire et Moléculaire UMR 8544 CNRS, Ecole Normale Supérieure, 75230 Paris Cedex 05, France

Despite the marked influence on neuronal physiology of the low-voltage activated T-type Ca²⁺ 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 ± 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 ATPS. 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 ± 143 msec and 4.9 ± 1.1 sec, respectively, at 25°C). The resulting apparent voltage sensitivity of this regulation follows the voltage dependence of the current steady-state 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.

Key words: facilitation; phosphorylation; potentiation; thalamus; current; T-type; calcium

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Received Nov 21, 2003; revised May 10, 2004; accepted May 10, 2004.

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