title: Ins and outs of T-channel structure function.
abstract: We review the ins and outs of T-channel structure, focusing on the extracellular high-affinity metal-binding site and intracellular loops. The high-affinity metal-binding site was localized to repeat I of Cav3.2. Interestingly, a similar binding site was found in the high voltage-activated Cav2.3 channel where it controls the channels' voltage dependence. Histidine at position 191 has a particularly interesting role in the high-affinity binding site, and its modification plays an important role in channel regulation by pharmacological agents that alter redox reactions. The intracellular loop connecting repeats I and II plays two important roles in Cav3.2 properties: one, its gating; and two, its surface expression. These studies have also identified a highly conserved intracellular gating brake that is predicted to form a helix-loop-helix structure. We conclude that the gating brake establishes important contacts with the gating machinery, thereby stabilizing a closed state of T-channels. This interaction is disrupted by depolarization, allowing the S6 segments to open and allowing Ca(2+) ions to flow through. Studies in cultured hippocampal neurons provided novel insights into how mutations found in idiopathic generalized epilepsy patients increase seizure susceptibility by both altering T-current pacemaker currents and by activating Ca-activated transcription factors that regulate dendritic arborization. These studies reveal novel roles for T-channels to control cellular physiology.
authors: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA, eperez@virginia.edu.
authors: Edward
authors: E
authors: Perez-Reyes
authors: Jung-Ha
authors: JH
authors: Lee
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000502:physiology*; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D017433:Protein Structure, Secondary
chemical_list: D020747:Calcium Channels, T-Type