Boiko N, Kucher V, Eaton BA, Stockand JD Inhibition of Neuronal Degenerin/Epithelial Na+ Channels by the Multiple Sclerosis Drug 4-Aminopyridine.J Biol Chem. 2013 [Epub ahead of print]
The voltage-gated K+ (Kv) channel blocker, 4-aminopyridine (4-AP), is used to target symptoms of the neuroinflammatory disease, multiple sclerosis (MS). By blocking Kv channels, 4-AP facilitates action potential conduction and neurotransmitter release in pre-synaptic neurons lessening the effects of demyelination. Because they conduct inward Na+ and Ca+ currents that contribute to axonal degeneration in response to inflammatory conditions, acid-sensing ion channels (ASICs) contribute to the pathology of MS. Consequently, ASICs are emerging as disease-modifying targets in MS. Surprisingly, as first demonstrated here, 4-AP inhibits neuronal Deg/ENaC channels, including ASIC and BLINaC. This effect is specific for 4-AP as compared to its heterocyclic base, pyridine, and the related derivative, 4-methylpyridine; and akin to the actions of 4-AP on the structurally unrelated Kv channels, dose- and voltage-dependent. 4-AP has differential actions on distinct ASICs, strongly inhibiting ASIC1a channels expressed in central neurons but being without effect on ASIC3, which is enriched in peripheral sensory neurons. The voltage-dependence of the 4-AP block and the single binding site for this inhibitor are consistent with 4-AP binding in the pore of Deg/ENaC channels as it does Kv channels, suggesting a similar mechanism of inhibition in these two classes of channels. These findings argue that effects on both Kv and Deg/ENaC channels should be considered when evaluating the actions of 4-AP. Importantly, the current results are consistent with 4-AP influencing the symptoms of MS as well as the course of the disease because of inhibitory actions on Kv and ASIC channels, respectively.
When nerves fire to transmit signals sodium is pumped out of the nerve and potassium is pumped in making an electrical charge difference to the nerve cell. Blocking Potassium channels helps keep nerves firing and counteracts the effects of demyelination. Hence it can help with symptoms of MS. However this study suggests that in addition to effects on potassium channels that move potassium in and out of the cell, it suggests that Fampridine/Fampyra may also block other channels, that have been implicated in part of the problem in progression. Therefore, in addition to an improvement on walking it may have a positive effect on walking. This is good news, but the question is where is the proof that it has any of this beneficial activity? This is just conjecture and one could make an argument for other scenarios. Amiloride is a drug that inhibits ASIC1 and this will be tested in progressive MSers soon.