Evolutionary History of Voltage-Gated Sodium Channels

Abstract

Every cell within living organisms actively maintains an intracellular Na concentration that is 10-12 times lower than the extracellular concentration. The cells then utilize this transmembrane Na concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising voltage-gated sodium channels (Nas) is essential for such signaling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another. Nas were first predicted in squid and were later identified through molecular biology in the electric eel. Since then, these proteins have been discovered in organisms ranging from bacteria to humans. Recent research has succeeded in decoding the amino acid sequences of a wide variety of Na family members, as well as the three-dimensional structures of some. These studies and others have uncovered several of the major steps in the functional and structural transition of Na proteins that has occurred along the course of the evolutionary history of organisms. Here we present an overview of the molecular evolutionary innovations that established present-day Na α subunits and discuss their contribution to the evolutionary changes in animal bodies.

Cell-Adhesion Properties of β-Subunits in the Regulation of Cardiomyocyte Sodium Channels

“…The neuronal Nav channels localised within the T-tubules are predominantly associated with the β1 and β3-subunits [ 5 ]. These Nav α-subunits all lack a glycosylation site in their DI, S5-P extracellular loop, equivalent to Asn319 in Nav1.5 [ 9 ]. Hence, it is likely that the β1 and β3 Ig domains will bind onto these Nav α-subunits in a manner more like Nav1.7 than Nav1.5 ( Figure 4 A,B).…”

“…The movement of the S4 helices in response to changes in membrane potential is transmitted to helices S5 and S6 of each domain. This leads to the transient opening and subsequent inactivation of the channel pore [ 8 , 9 ]. High-resolution structures obtained by cryogenic electron microscopy (cryo-EM), for the heart-specific Nav1.5 α-subunit, the skeletal muscle channel Nav1.4 and the neuronal channels Nav1.2 and Nav1.7 show that the four domains surround the central pore with four-fold pseudosymmetry.…”

Action Potentials and Na+ voltage-gated ion channels in Placozoa

“…Na + -dependent action potentials in placozoans could be mediated by two classes of voltage-gated cation channels (Ca v and Na v , Fig.3B ) with a shared topology containing 24 transmembrane (TM) helices, which are four repeats of 6TM domains[36,37,40,49,50] evolved from prokaryotic ancestors[37,51]. One sodium-conducting Ca v 3 and two Na v channels in Trichoplax have been reported[6,36,37,50].…”

“…Some medusozoans (Cnidaria) and bilaterians (including humans) independently developed Na v 1-type channels with very fast activation kinetics and high selectivity for Na + vs. Ca 2+ [6,36,37,40,49,54]. This metazoan-specific innovation is associated with the presence of a single positively-charged lysine (K) in the selective filter region, leading to DE K A and D K EA motifs for humans and jellyfishes, respectively[36,37,40,49,51]. In two species of Hoilungia (H4 and H13 haplotypes), we also identified lysine (K) but in the 4th vs. the 2nd positions (as in jellyfishes) of the second domain (DII, Fig.…”

Neuron subtype-specific effector gene expression in the Motor Ganglion of Ciona

“…We therefore focused on these, hoping to identify candidate effectors of ddN development and function. For instance, we detected an enrichment for transcripts from the Sodium voltage-gated channel subunit alpha a gene (Scna.a, KH.C9.462, LogFC = 1.6), encoding a voltage gated sodium channel orthologous to vertebrate NaV1 channels (Katsuyama et al, 2005;Nishino and Okamura, 2018;. By ISH, we found that Scna.a is upregulated specifically in the ddN and in MN1, but not in MGIN2 nor in any other MG neurons at around stage 23 (~15.5 hpf at 16°C), when most are differentiating (Fig 2E).…”