title: Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Ca(v)2.3 calcium channels.
abstract: Here, we describe a new mechanism by which glutamate (Glu) and trace metals reciprocally modulate activity of the Ca(v)2.3 channel by profoundly shifting its voltage-dependent gating. We show that zinc and copper, at physiologically relevant concentrations, occupy an extracellular binding site on the surface of Ca(v)2.3 and hold the threshold for activation of these channels in a depolarized voltage range. Abolishing this binding by chelation or the substitution of key amino acid residues in IS1-IS2 (H111) and IS2-IS3 (H179 and H183) loops potentiates Ca(v)2.3 by shifting the voltage dependence of activation toward more negative membrane potentials. We demonstrate that copper regulates the voltage dependence of Ca(v)2.3 by affecting gating charge movements. Thus, in the presence of copper, gating charges transition into the "ON" position slower, delaying activation and reducing the voltage sensitivity of the channel. Overall, our results suggest a new mechanism by which Glu and trace metals transiently modulate voltage-dependent gating of Ca(v)2.3, potentially affecting synaptic transmission and plasticity in the brain.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA. alexsh@stanford.edu
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Shcheglovitov
authors.forename: Iuliia
authors.initials: I
authors.lastname: Vitko
authors.forename: Roman M
authors.initials: RM
authors.lastname: Lazarenko
authors.forename: Peihan
authors.initials: P
authors.lastname: Orestes
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D055592:Biophysical Phenomena; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020908:Calcium Channels, R-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D051381:Rats; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014131:Trace Elements / Q000494:pharmacology
chemical_list: C500545:CACNA1B protein, human; C423009:CACNA1E protein, human; D020864:Calcium Channels, N-Type; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D011994:Recombinant Proteins; D014131:Trace Elements; D018698:Glutamic Acid; D003300:Copper; D005998:Glycine; C100184:tricine