Sandbox WWC3: Difference between revisions

[[Sodium channels]] <ref name ="sod">https://en.wikipedia.org/wiki/Sodium_channel</ref> are voltage gated integral membrane proteins found in muscles and neurons that selectively allow for the diffusion of sodium ions across the membrane. These proteins are important for all cells but are specifically responsible for initiating electrical signaling in these cells, which causes action potentials or muscle contractions<ref name = "crystal">doi: 10.1038/nature10238</ref> . Sodium channels and are commonly targets of drugs and mutations can cause serious disease. Each sodium channel is composed of three subunits: the alpha subunit, which is the transmembrane ion channel <ref name = "sod"/>, and two beta subunits that modulate channel gating and regulate the channel expression in the membrane <ref name ="beta">PMID: 11486343</ref>. The alpha subunit is able to function independently of the beta subunit<ref name = "beta"/> .

Sodium channels initiate action potentials in nerve and muscle cells. These electrical signals initiate the contraction of muscles and the release of neurotransmitters. The electrical signal is propagated when the sodium channel allows the influx of sodium ions. These positively charged ions depolarize the resting membrane potential of -70mV to +40mV, which creates the electrical signal that is sent along the length of the cell.The initial influx of sodium ions is often activated by the binding of a neurotransmitter to receptors on the post-synaptic membrane <ref>https://en.wikipedia.org/wiki/Neurotransmission</ref>. Then, as the sodium ions depolarize the membrane potential. more sodium channels open, and the action potential moves along the length of the muscle or nerve. The channels inactivate after 1-2ms and the depolarization is then reversed by the efflux of potassium ions out of potassium channel<ref name ="physio"/>. This information was first discovered by Hodgkin and Huxley in 1952<ref name ="physio"/>. For more information on the role of sodium channels in electrical signaling, click [https://en.wikipedia.org/wiki/Action_potential here].

As noted above, the sodium channel consists of an alpha and two beta subunits. However, the alpha subunit is the only part necessary for the function of the channel <ref name = "sod"/>. The alpha subunit, depicted right, consists of four repeating structures, named I through IV <ref name ="struct"> DOI: 10.1111/j.1469-7793.1998.647bp.x </ref> and shown in different colors <scene name='69/696300/Right_one/1'>here</scene>. These structures consist of six transmembrane alpha helices named S1 through S6 <ref name = "struct"/>. Interestingly, each repeating subunit resembles a bacterial K⁺ channel <ref name = "struct"/>. These subunits fold together to form a central pore, and this complete structure resembles a bacterial Ca2+ channel <ref name = "struct"/>.

The S1 through S4 segments make up the gating mechanism <ref name= "crystal"/>. In particular,the S4 segments consist of repeated motifs of a positively charged residue (usually Arg) followed by two hydrophobic residues <ref name= "crystal"/>. This alpha helix is exposed to the membrane electric field, and in response to a depolarization, it is displaced outwards <ref name= "crystal"/>. This causes the channel to open. S4 segments can be seen in red <scene name='69/696300/S4/1'>here</scene>. Surprisingly, each S4 chain does not contribute equally to the gating of this channel. A mutation in one chain may have a much larger effect than a mutation in another S4 chain <ref name= "crystal"/>.. However, these S4 segments are merely sensors. The actual gating mechanism is still up for debate, with the leading contender being the S6 segment. This mechanism would be similar to the gating of the K+ channel <ref name = "struct"/>. The outward movement of the S4 segment moves the S4-S5 linker, which pulls the S5-S6 segments and opens the pore <ref name= "crystal"/>. Overall, the voltage sensing domain makes a rolling motion of the S4-S5 linker around the pore <ref name= "crystal"/>. The S4-S5 linker can be seen <scene name='69/696300/S4_s5_linker/2'>here</scene>.

This channel conducts sodium at nearly the rate of free diffusion <ref name= "crystal"/>. This pore consists of an outer funnel-like vestibule, a selectivity filter, a central cavity, and an intracellular activation gate <ref name= "crystal"/>. Unlike the K+ channel, the Na+ channel conducts sodium ions that are hydrated with four water molecules <ref name= "crystal"/>. Much like with the gating mechanism, each domain does not contribute equally to the selectivity of the pore <ref name= "struct"/>, but the channel selects for sodium 100x greater than it selects for any other ion <ref name= "struct"/>.  

It is likely that the sodium ion can get much closer to the channel than a larger K+ ion. When the ion reaches this distance, there is a more efficient removal of water and the sodium interacts with the Glu117 side chains. Two side chains interact directly with the sodium ion and two side chains form hydrogen bonds with the water molecules <ref name= "crystal"/>. The pore is made up of THR 175, LEU 176, GLU 177 and SER 178 <ref name= "crystal"/>. The GLU side chains act as hydrogen bond acceptors two in-plane molecules surrounding the sodium ion<ref name= "crystal"/>. The other two water molecules would be axial to the sodium ion<ref name= "crystal"/>. Full rehydration would occur when the ion moves next to the LEU and THR residues<ref name= "crystal"/>. Full rehydration then allows the sodium ion to enter the cytoplasm<ref name= "crystal"/>.