The voltage-gated Na+ channel Nav1.8 contains an ER-retention/retrieval signal antagonized by the beta3 subunit.
Voltage-gated Na(+) channel (Na(v)) 1.8 contributes to the majority of the Na(+) current that underlies the depolarizing phase of action potentials. Na(v)1.8 is mainly distributed intracellularly and its current amplitude can be enhanced by the beta3 subunit. However, little is known about the mechanisms underlying its intracellular retention and the effects mediated by the beta3 subunit. Here, we show that the beta3 subunit promotes surface expression of Na(v)1.8 by masking its endoplasmic reticulum (ER)-retention/retrieval signal. The RRR motif in the first intracellular loop of Na(v)1.8 is responsible for retaining Na(v)1.8 in the ER and restricting its surface expression. The beta3 subunit facilitates surface expression of Na(v)1.8. The intracellular C-terminus of the beta3 subunit interacts with the first intracellular loop of Na(v)1.8 and masks the ER-retention/retrieval signal. Mutation of the RRR motif results in a significant increase in surface expression of Na(v)1.8 and abolishes the beta3-subunit-mediated effects. Thus, the beta3 subunit regulates surface expression of Na(v)1.8 by antagonizing its ER-retention/retrieval signal. These results reveal a novel mechanism for the effect of the Na(+) channel beta subunits on the alpha subunits.
Zhang
Zhen-Ning
ZN
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, People's Republic of China.
Li
Qian
Q
Liu
Chao
C
Wang
Hai-Bo
HB
Wang
Qiong
Q
Bao
Lan
L
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism*
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D021382:Protein Sorting Signals; D021122:Protein Subunits; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; D015222:Sodium Channels