title: Erbin enhances voltage-dependent facilitation of Ca(v)1.3 Ca2+ channels through relief of an autoinhibitory domain in the Ca(v)1.3 alpha1 subunit.
abstract: Ca(v)1.3 (L-type) voltage-gated Ca2+ channels have emerged as key players controlling Ca2+ signals at excitatory synapses. Compared with the more widely expressed Ca(v)1.2 L-type channel, relatively little is known about the mechanisms that regulate Ca(v)1.3 channels. Here, we describe a new role for the PSD-95 (postsynaptic density-95)/Discs large/ZO-1 (zona occludens-1) (PDZ) domain-containing protein, erbin, in directly potentiating Ca(v)1.3. Erbin specifically forms a complex with Ca(v)1.3, but not Ca(v)1.2, in transfected cells. The significance of erbin/Ca(v)1.3 interactions is supported by colocalization in somatodendritic domains of cortical neurons in culture and coimmunoprecipitation from rat brain lysates. In electrophysiological recordings, erbin augments facilitation of Ca(v)1.3 currents by a conditioning prepulse, a process known as voltage-dependent facilitation (VDF). This effect requires a direct interaction of the erbin PDZ domain with a PDZ recognition site in the C-terminal domain (CT) of the long variant of the Ca(v)1.3 alpha1 subunit (alpha1 1.3). Compared with Ca(v)1.3, the Ca(v)1.3b splice variant, which lacks a large fraction of the alpha1 1.3 CT, shows robust VDF that is not further affected by erbin. When coexpressed as an independent entity with Ca(v)1.3b or Ca(v)1.3 plus erbin, the alpha1 1.3 CT strongly suppresses VDF, signifying an autoinhibitory function of this part of the channel. These modulatory effects of erbin, but not alpha1 1.3 CT, depend on the identity of the auxiliary Ca2+ channel beta subunit. Our findings reveal a novel mechanism by which PDZ interactions and alternative splicing of alpha1 1.3 may influence activity-dependent regulation of Ca(v)1.3 channels at the synapse.
authors.affiliation: Department of Pharmacology and Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Calin-Jageman
authors.forename: Kuai
authors.initials: K
authors.lastname: Yu
authors.forename: Randy A
authors.initials: RA
authors.lastname: Hall
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001665:Binding Sites; D001667:Binding, Competitive; D001923:Brain Chemistry; D015220:Calcium Channels / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000502:physiology*; D002352:Carrier Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000737:chemistry; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; C517630:erbin protein, rat; C093712:Cacna1d protein, rat