What is the structure and function of fast voltage-gated sodium (Na+) channels?

Structure and Function of Fast Voltage-Gated Sodium Channels

Structural Organization

Fast voltage-gated sodium channels consist of a large α-subunit (260 kDa) that forms the functional pore, associated with auxiliary β-subunits (β1 at 36 kDa and β2 at 33 kDa) that modulate gating properties. 1

α-Subunit Architecture

• The α-subunit comprises four homologous domains (I-IV), each containing six transmembrane α-helices (S1-S6) plus additional membrane-associated segments (SS1/SS2) 1
• The S4 segments in each domain function as voltage sensors containing positively charged residues that move through the transmembrane electric field in response to voltage changes 1, 2
• The S5 and S6 segments from all four domains, along with the SS1/SS2 segments between them, form the ion-conducting pore 1
• Recent structural evidence demonstrates that the S4 segment moves intracellularly with three gating charges passing through the transmembrane electric field, forming an elbow that connects to the S4-S5 linker 2

β-Subunit Contributions

• β-subunits alter voltage dependence of both activation and inactivation, change sarcolemmal expression levels, and contribute to interactions with the extracellular matrix 3
• The β-subunits contain immunoglobulin-like folds in their extracellular domains that interact with extracellular proteins 1

Quaternary Structure

• Contrary to traditional views, sodium channels actually assemble and function as dimers rather than monomers, with α-subunits physically interacting and exhibiting coupled gating mediated by 14-3-3 proteins 4

Functional Mechanisms

Voltage-Dependent Activation

The channel transitions from resting to activated state through a "sliding helix" mechanism where the S4 voltage sensors move outward in response to depolarization, pulling on the S4-S5 linker to open the activation gate formed by the S6 segments. 2

• In the resting state (at deeply negative membrane potentials), the S4 segment is drawn intracellularly, forming a tight collar around the S6 activation gate that prevents opening 2
• Upon depolarization, voltage sensors detect the change and trigger conformational changes that open the pore 5

Fast Inactivation

The intracellular loop connecting domains III and IV forms the inactivation gate, which folds into and occludes the pore within 1 millisecond of channel opening. 1

• This "ball-and-chain" mechanism blocks the pore from the intracellular side during sustained depolarization 6
• Mutations affecting fast inactivation can prolong sodium current during phase 0, leading to conditions like long QT syndrome type 3 where delayed inactivation causes persistent inward sodium current 7

Slow Inactivation

• Repetitive or continuous stimulation produces rate-dependent decrease of sodium current through slow inactivation, which may continue until the channel fully shuts down 6
• This process occurs on a slower timescale than fast inactivation and involves different structural rearrangements 6

Regulation and Modulation

Protein Phosphorylation

• Activation of protein kinase C (PKC) through muscarinic acetylcholine receptors slows inactivation and reduces peak sodium currents by phosphorylating sites in the inactivation gate and the intracellular loop between domains I and II 1
• cAMP-dependent protein kinase phosphorylation reduces peak sodium currents through sites in the intracellular loop between domains I and II 1
• Modulation by PKC and cAMP-dependent protein kinase is convergent—phosphorylation of the inactivation gate by PKC is required before phosphorylation of other sites can reduce peak currents 1

G-Protein Regulation

• Activation of G protein-coupled receptors causes negative shifts in voltage dependence of activation and inactivation 1
• Overexpression of G protein βγ subunits induces persistent sodium currents 1

Macromolecular Complexes

• Ion channels exist as part of extensive macromolecular complexes that allow rapid modulation in response to extrinsic factors 3
• Channel regulation occurs on multiple temporal and spatial scales, involving targeting to specific membrane locations and subsequent regulation by second messengers, hormones, neurotransmitters, humoral factors, kinases, and phosphatases 3

Clinical Relevance

Channelopathies

• Novel long-QT syndrome and Brugada syndrome susceptibility genes involve channel-interacting proteins including caveolin-3 (LQT9), sodium channel β-subunit (LQT10), yotiao (LQT11), and glycerol-3-phosphate dehydrogenase 1-like protein (BrS2) 3

Drug Interactions

• Antiepileptic drugs (phenytoin, carbamazepine, lamotrigine) and local anesthetics bind preferentially to the inactivated state of sodium channels at a common receptor site in the pore formed by transmembrane segment S6 in domain IV 1
• This use-dependent block is enhanced by depolarization, increasing inhibition in depolarized tissue such as epileptic foci 1