Distinct domains of the sodium channel β3-subunit modulate channel-gating kinetics and subcellular location

• Published in: Biochemical journal 2005-12, Vol.392 (3), p.519-526
• Main Authors: Yu, Esther J., Ko, Seong-Hoon, Lenkowski, Paul W., Pance, Alena, Patel, Manoj K., Jackson, Antony P.
• Format: Article
• Language: English
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20050518

Electrical excitability in neurons depends on the expression and activity of voltage-gated sodium channels in the neuronal plasma membrane. The ion-conducting α-subunit of the channel is associated with auxiliary β-subunits of which there are four known types. In the present study, we describe the first detailed structure/function analysis of the β3-subunit. We correlate the effect of point mutations and deletions in β3 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 β3 to the plasma membrane when expressed with the α-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 β3 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 β3 molecule can traverse the secretory pathway independently of the α-subunit.