Sandbox WWC3: Difference between revisions

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].

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, 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 entry 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 additional 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"/>.

To see the selectivity filter, click <scene name='69/696300/Selectivity_pore/2'>here</scene>. THR 175 is blue, LEU 176 is yellow, GLU 177 is red and SER 178 is black.

This image shows the crystal structure of the selectivity filter <ref name= "crystal"/>.

There are nine different α subunits named NaV1.1 through NAV1.9<ref name = "sod"/>. Genes are SCN1 through SCN11<ref name = "sod"/>. These structures differ in their sequence and kinetics<ref name = "sod"/>. As stated above, the α subunit is necessary to the function of the channel and can function independently of the β subunit. You can find the structures and more information below.

* [https://en.wikipedia.org/wiki/Nav1.1 NaV1.1]: found in central and peripheral neurons and myocytes. Click <scene name='69/696300/Nav1_1/1'>here</scene> for the structure of the NaV1.1 inactivation gate<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.2 NaV1.2]: found in central and peripheral neurons. Click <scene name='69/696300/Nav1_2/1'>here</scene> for the structure of the NaV1.2 C terminal domain in complex with FGF13U and Ca2+/calmodulin<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/SCN3A NaV1.3]: found in central and peripheral neurons and cardiac myocytes<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.4 NaV1.4]: found in skeletal muscle<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.5 NaV1.5]: found in cardiac myocytes, uninnervated skeletal muscle, central neurons, gastrointestinal smooth muscle cells, and interstitial cells of Cajal. Click <scene name='69/696300/Nav1_5/1'>here</scene> for the structure of the NaV1.5 C terminal domain in complex with FGF12B and Ca2+/calmodulin<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/SCN8A NaV1.6]: found in central neurons, dorsal root ganglia, peripheral neurons, heart and glial cells<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.7 NaV1.7]: found in dorsal root ganglia, sympathetic neurons, Schwann cells and neuroendocrine cells<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.8 NaV1.8]: found in dorsal root ganglia<ref name = "sod"/>.

* [https://en.wikipedia.org/wiki/Nav1.9 NaV1.9]: found in dorsal root ganglia<ref name = "sod"/>.

Beta subunits function in channel gating, channel expression and form links to the cytoskeleton <ref name = "sod"/>. There are four different beta subunits named NaVβ1 through NaVβ4 and the genes are named SCN1B through SCN4B<ref name = "sod"/>.

*[https://en.wikipedia.org/wiki/SCN1B NaVβ1]: Assembles with NaV1.1 and NaV1.7 and found in central and peripheral neurons, skeletal muscle, heart and glial cells<ref name = "sod"/>.

*[https://en.wikipedia.org/wiki/SCN2B NaVβ2]: Assembles with NaV1.1, NaV1.2, NaV1.5 and NaV1.7 and found in central and peripheral neurons, heart and glial cells<ref name = "sod"/>.

*[https://en.wikipedia.org/wiki/SCN3B NaVβ3]: Assembles with NaV1.1, NaV1.3 and NaV1.5 and found in the central and peripheral neurons, adrenal gland and heart<ref name = "sod"/>.

*[https://en.wikipedia.org/wiki/SCN4B NaVβ4]: Assembles with NaV1.1, NaV1.2, and NaV1.5 and found in the heart, skeletal muscles, central and peripheral neurons<ref name = "sod"/>.

Diseases caused by mutations in sodium channels can come in many forms. Some mutations affect skeletal, cardiac or smooth muscle, while others affect neural function. Common diseases include Long QT Syndrome, Hyperkalemic Periodic Paralysis, Hypokalemic Periodic Paralysis, Myotonia Fluctuans and Myotonia Permanens among many others <ref name ="dis">http://neuromuscular.wustl.edu/mother/chan.html#SCN4A</ref>. 

This disease causes seizures, fainting or sudden death from cardiac arrhythmias and is caused my a mutation in the SCN5A gene, or the gene that encodes the NaV1.5 alpha subunit <ref name ="QT">DOI: 10.1016/0092-8674(95)90359-3</ref><ref name ="Long">http://www.mayoclinic.org/diseases-conditions/long-qt-syndrome/basics/definition/con-20025388</ref>. It was found that this deletion includes the region that codes for Lys-1505, Pro-1506 and Gln-1507. These residues occur in the cytoplasmic linker between domain III and domain IV <ref name = "QT"/>

Hyperkalemic period paralysis is caused by the mutations Thr704Met; Ser906Thr; Ala1156Thr; Met1360Val; Arg1448Cys and/or Met1592Val<ref name = "Hyper">http://neuromuscular.wustl.edu/mother/activity.html#hrpp</ref>. These mutations cause periodic or permanent weakness<ref name = "Hyper"/>. Physiologically, this is a gain of function mutation. During rest after exercise, or after eating foods rich in K+, the extracellular K+ increases, which mildly depolarizes the membrane<ref name = "Hyper"/>. This causes abnormal Na+ channels to open, and they are unable to inactivate <ref name = "Hyper"/>. This sustained depolarization of the membrane causes even more abnormal Na+ channels to open and ultimately this leads to loss of excitability and weakness <ref name = "Hyper"/>. This symptom usually appears within the first decade of life and can be aggravated by exercise, cold, potassium loading, fasting or pregnancy <ref name = "Hyper"/>. Attacks are usually brief and do not need treatment<ref name = "Hyper"/>.

Hypokalemic periodic paralysis is caused by the mutations Arg669His, Arg672His, Arg672Gly, Arg672Ser, R1132Q, P1158S in the S4 segment of the NaV1.4 sodium channel. <ref name = "Hypo">http://neuromuscular.wustl.edu/mtime/mepisodic.html#hopp</ref>.It is a loss of function mutation resulting in attacks of muscular weakness <ref name = "Hypo"/>. This disorder is a dominant mutation<ref name = "Groome">DOI: 10.1093/brain/awu015</ref>. Factors that trigger these episodes include meals rich in carbohydrates, rest after exercise, early morning hours, and emotional stress <ref name = "Groome"/>.  Most mutations are in two the Arg residues closes to the extracellular side of the S4 segment <ref name = "Groome"/>. These mutations cause a leak current of Na+ ions inward, which is called an "omega" current <ref name = "Groome"/>. This inward current causes the K+ channels to not be effective and results in muscle weakness <ref name = "Groome"/>.

Myotonia fluctuans is due to the G1306A mutation in the NaV1.4 sodium channel<ref name = "Fluct">http://neuromuscular.wustl.edu/mother/activity.html#mf</ref>. All mutations at the 1306 site cause reduced channel inactivation due to the fact that they are located on the hinge of the channel inactivation gate <ref name = "Fluct"/>. This disease is characterized by the inability to relax voluntary muscle after vigorous exercise. However, the condition fluctuates day to day, hence the name<ref name = "Fluct"/>.

Myotonia permanens is similar to myotonia fluctuans in that it causes the inability to relax voluntary muscle<ref name = "Fluct"/>. However, this disease is caused by the Gly1306Glu mutation<ref name = "Fluct"/>. Again, this mutation causes reduced channel inactivation due to the location of the mutation on the inactivation gate <ref name = "Fluct"/>. Severe myotonia permanens may interfere with respiration and is worsened after eating K+ rich foods <ref name = "Fluct"/>.