title: Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels.
abstract: Excitation-contraction (EC) coupling in skeletal muscle depends upon trafficking of CaV1.1, the principal subunit of the dihydropyridine receptor (DHPR) (L-type Ca(2+) channel), to plasma membrane regions at which the DHPRs interact with type 1 ryanodine receptors (RyR1) in the sarcoplasmic reticulum. A distinctive feature of this trafficking is that CaV1.1 expresses poorly or not at all in mammalian cells that are not of muscle origin (e.g., tsA201 cells), in which all of the other nine CaV isoforms have been successfully expressed. Here, we tested whether plasma membrane trafficking of CaV1.1 in tsA201 cells is promoted by the adapter protein Stac3, because recent work has shown that genetic deletion of Stac3 in skeletal muscle causes the loss of EC coupling. Using fluorescently tagged constructs, we found that Stac3 and CaV1.1 traffic together to the tsA201 plasma membrane, whereas CaV1.1 is retained intracellularly when Stac3 is absent. Moreover, L-type Ca(2+) channel function in tsA201 cells coexpressing Stac3 and CaV1.1 is quantitatively similar to that in myotubes, despite the absence of RyR1. Although Stac3 is not required for surface expression of CaV1.2, the principle subunit of the cardiac/brain L-type Ca(2+) channel, Stac3 does bind to CaV1.2 and, as a result, greatly slows the rate of current inactivation, with Stac2 acting similarly. Overall, these results indicate that Stac3 is an essential chaperone of CaV1.1 in skeletal muscle and that in the brain, Stac2 and Stac3 may significantly modulate CaV1.2 function.
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Alexander
authors.initials: A
authors.lastname: Polster
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Stefano
authors.initials: S
authors.lastname: Perni
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Hicham
authors.initials: H
authors.lastname: Bichraoui
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 Kurt.Beam@ucdenver.edu.
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Beam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020746:Calcium Channels, L-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D056966:Excitation Contraction Coupling / Q000502:physiology; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C514350:CACNA1C protein, mouse; C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C583601:STAC3 protein, mouse; C484465:Stac protein, mouse; C556676:Stac2 protein, mouse; C000592747:ryanodine receptor 1, mouse
keywords: L-type Ca2+ channel; Stac adaptor protein; excitation–contraction coupling