title: Distinct domains of the sodium channel beta3-subunit modulate channel-gating kinetics and subcellular location.
abstract: Electrical excitability in neurons depends on the expression and activity of voltage-gated sodium channels in the neuronal plasma membrane. The ion-conducting alpha-subunit of the channel is associated with auxiliary beta-subunits of which there are four known types. In the present study, we describe the first detailed structure/function analysis of the beta3-subunit. We correlate the effect of point mutations and deletions in beta3 with the functional properties of the sodium channel and its membrane-targeting behaviour. We show that the extracellular domain influences sodium channel gating properties, but is not required for the delivery of beta3 to the plasma membrane when expressed with the alpha-subunit. In contrast, the intracellular domain is essential for correct subunit targeting. Our results reveal the crucial importance of the Cys21-Cys96 disulphide bond in maintaining the functionally correct beta3 structure and establish a role for a second putative disulphide bond (Cys2-Cys24) in modulating channel inactivation kinetics. Surprisingly, our results imply that the wild-type beta3 molecule can traverse the secretory pathway independently of the alpha-subunit.
authors.affiliation: Department of Biochemistry, The University of Cambridge, Downing Site, Tennis Court Road, Cambridge CB2 1QW, UK.
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Yu
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Ko
authors.forename: Paul W
authors.initials: PW
authors.lastname: Lenkowski
authors.forename: Alena
authors.initials: A
authors.lastname: Pance
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.forename: Antony P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D017353:Gene Deletion; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D015222:Sodium Channels