title: Ca2+ controls gating of voltage-gated calcium channels by releasing the β2e subunit from the plasma membrane.
abstract: Voltage-gated calcium (Cav) channels, which are regulated by membrane potential, cytosolic Ca(2+), phosphorylation, and membrane phospholipids, govern Ca(2+) entry into excitable cells. Cav channels contain a pore-forming α1 subunit, an auxiliary α2δ subunit, and a regulatory β subunit, each encoded by several genes in mammals. In addition to a domain that interacts with the α1 subunit, β2e and β2a also interact with the cytoplasmic face of the plasma membrane through an electrostatic interaction for β2e and posttranslational acylation for β2a. We found that an increase in cytosolic Ca(2+) promoted the release of β2e from the membrane without requiring substantial depletion of the anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) from the plasma membrane. Experiments with liposomes indicated that Ca(2+) disrupted the interaction of the β2e amino-terminal peptide with membranes containing PIP2 Ca(2+) binding to calmodulin (CaM) leads to CaM-mediated inactivation of Cav currents. Although Cav2.2 coexpressed with β2a required Ca(2+)-dependent activation of CaM for Ca(2+)-mediated reduction in channel activity, Cav2.2 coexpressed with β2e exhibited Ca(2+)-dependent inactivation of the channel even in the presence of Ca(2+)-insensitive CaM. Inducible depletion of PIP2 reduced Cav2.2 currents, and in cells coexpressing β2e, but not a form that lacks the polybasic region, increased intracellular Ca(2+) further reduced Cav2.2 currents. Many hormone- or neurotransmitter-activated receptors stimulate PIP2 hydrolysis and increase cytosolic Ca(2+); thus, our findings suggest that β2e may integrate such receptor-mediated signals to limit Cav activity.
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
authors.forename: Dong-Il
authors.initials: DI
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
authors.forename: Hae-Jin
authors.initials: HJ
authors.lastname: Kweon
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Yongsoo
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Ecological Science, College of Ecology and Environment, Kyungpook National University, Kyungbuk 742-711, Korea.
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea. bcsuh@dgist.ac.kr.
authors.forename: Byung-Chang
authors.initials: BC
authors.lastname: Suh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism
chemical_list: C500963:Cacna1b protein, mouse; C491528:Cacnb2 protein, mouse; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D019269:Phosphatidylinositol 4,5-Diphosphate; D002118:Calcium