Ca2+ entry into neuronal cells is modulated by the activation of numerous G-protein-coupled receptors (GPCRs). Much effort has been invested in studying direct G-protein-mediated inhibition of voltage-dependent CaV2 Ca2+ channels. This inhibition occurs through a series of convergent modifications in the biophysical properties of the channels. An integrated view of the structural organization of the Gbetagamma-dimer binding-site pocket within the channel is emerging. In this review, we discuss how variable geometry of the Gbetagamma binding pocket can yield distinct sets of channel inhibition. In addition, we propose specific mechanisms for the regulation of the channel by G proteins that take into account the regulatory input of each Gbetagamma binding element

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.

T-type calcium channels (the Ca V 3 channel family) are involved in defining the resting membrane potential and in neuronal activities such as oscillations and rebound depolarization. Their physiological roles depend upon the channel activation and inactivation kinetics. A fast inactivation that stops the ionic flux of calcium in tens of milliseconds has already been described in both native and heterologously expressed channels. Here, using HEK 293 cells expressing the rat Ca V 3.1 channel and whole-cell voltage clamp, we investigate an additional inactivation process, which can be distinguished from the previously described fast inactivation by its slow time course of recovery from inactivation (τ = 1 s) and by its sensitivity to external calcium. Steady-state slow inactivation is voltage dependent around the resting membrane potential (the potential of half-inactivation (V 0.5 ) = −70 mV, slope factor = 7.4 mV) and can reduce the calcium current by up to 50%. Near resting potential, the slow inactivation displays a half-time of induction of tens of seconds. The slow inactivation therefore modulates the availability of T-type calcium channels depending upon recent cell history, providing a mechanism to store information in a time scale of seconds.

N ombre de mécanismes cellulaires dépendent d'entrées de calcium survenant au potentiel de repos de la membrane. A titre d'exemples, citons dans le système nerveux, les potentiels d'action calciques ou les activités oscillatoires rythmiques comme celles du thalamus ; et pour les cellules non excitables, la capacitation des spermatozoïdes ou la sécrétion de certaines hormones. La variété de ces fonctions expliquent les nombreux travaux menés pour identifier des canaux qui laissent entrer les ions calcium préférentiellement aux ions sodium et potassium-cations majoritaires des milieux physiologiques intra-et extracellulaires-et s'ouvrent à des potentiels relativement hyperpolarisés contrairement aux autres canaux calciques (comme par exemple les canaux L du coeur sensibles aux dihydropyridines). Par ailleurs, ces canaux à bas seuil d'activité s'ouvrent transitoirement même si la dépolarisation est maintenue (d'où leur dénomination de canaux T). Trois canaux T(α1G, α1H et α1I ou Cav3.1, Cav3.2 et Cav3.3) (pour plus de détails, voir l'article de P. Lory et 989 Les entrées de calcium au voisinage du potentiel de repos : un rôle sur mesure pour les canaux T dans de multiples fonctions De nombreux processus physiologiques sous le contrôle du Ca 2+ intracellulaire surviennent à des potentiels membranaires proches du potentiel de repos. A ces potentiels, les canaux calcium de type T sont des acteurs privilégiés du contrôle calcique, capables d'engendrer soit un courant dépolarisant de grande amplitude mais transitoire, soit un courant de faible amplitude mais soutenu. Dans les deux cas, ces courants participent étroitement à l'homéostasie calcique intracellulaire et conditionnent l'intégration des signaux cellulaires. Le clonage en 1998-1999 par l'équipe de Perez-Reyes-et depuis par d'autres équipes-de trois canaux T permet d'espérer un progrès rapide des études au niveau cellulaire, de mieux comprendre les fonctions physiologiques et d'ouvrir un nouveau champ d'investigations à visée thérapeutique.

The document associated with this DOI has been withdrawn.