TY - JOUR
T1 - Structural basis of cytoplasmic nav1.5 and nav1.4 regulation
AU - Nathan, Sara
AU - Gabelli, Sandra B.
AU - Yoder, Jesse B.
AU - Srinivasan, Lakshmi
AU - Aldrich, Richard W.
AU - Tomaselli, Gordon F.
AU - Ben-Johny, Manu
AU - Amzel, L. Mario
N1 - Publisher Copyright:
© 2020 Nathan et al.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - Voltage-gated sodium channels (NaVs) are membrane proteins responsible for the rapid upstroke of the action potential in excitable cells. There are nine human voltage-sensitive NaV1 isoforms that, in addition to their sequence differences, differ in tissue distribution and specific function. This review focuses on isoforms NaV1.4 and NaV1.5, which are primarily expressed in skeletal and cardiac muscle cells, respectively. The determination of the structures of several eukaryotic NaVsbysingle-particle cryo-electron microscopy (cryo-EM) has brought new perspective to the study of the channels. Alignment of the cryo-EM structure of the transmembrane channel pore with x-ray crystallographic structures of the cytoplasmic domains illustrates the complementary nature of the techniques and highlights the intricate cellular mechanisms that modulate these channels. Here, we review structural insights into the cytoplasmic C-terminal regulation of NaV1.4 and NaV1.5 with special attention to Ca2+ sensing by calmodulin, implications for disease, and putative channel dimerization.
AB - Voltage-gated sodium channels (NaVs) are membrane proteins responsible for the rapid upstroke of the action potential in excitable cells. There are nine human voltage-sensitive NaV1 isoforms that, in addition to their sequence differences, differ in tissue distribution and specific function. This review focuses on isoforms NaV1.4 and NaV1.5, which are primarily expressed in skeletal and cardiac muscle cells, respectively. The determination of the structures of several eukaryotic NaVsbysingle-particle cryo-electron microscopy (cryo-EM) has brought new perspective to the study of the channels. Alignment of the cryo-EM structure of the transmembrane channel pore with x-ray crystallographic structures of the cytoplasmic domains illustrates the complementary nature of the techniques and highlights the intricate cellular mechanisms that modulate these channels. Here, we review structural insights into the cytoplasmic C-terminal regulation of NaV1.4 and NaV1.5 with special attention to Ca2+ sensing by calmodulin, implications for disease, and putative channel dimerization.
UR - http://www.scopus.com/inward/record.url?scp=85098472288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098472288&partnerID=8YFLogxK
U2 - 10.1085/jgp.202012722
DO - 10.1085/jgp.202012722
M3 - Review article
C2 - 33306788
AN - SCOPUS:85098472288
SN - 0022-1295
VL - 153
JO - Journal of General Physiology
JF - Journal of General Physiology
IS - 1
M1 - e202012722
ER -