Wu ZZ, Li DP, Chen SR, Pan HL
Aminopyridines potentiate synaptic and neuromuscular transmission by targeting voltage-activated calcium channel beta subunit. [JOURNAL ARTICLE]
J Biol Chem 2009 Oct 22.
Aminopyridines such as 4-aminopyridine (4-AP) are widely used as voltage-activated K+ (Kv) channel blockers and can improve neuromuscular function in patients with spinal cord injury, myasthenia gravis, or multiple sclerosis. Here we present novel evidence that 4-AP and several of its analogues directly stimulate high voltage-activated Ca2+ channels (HVACCs) in native neurons. 4-AP, 4-(aminomethyl)pyridine, 4-(methylamino)pyridine, and 4-di(methylamino)pyridine profoundly increase HVACC, but not T-type, currents in dissociated neurons from the rat dorsal root ganglion, superior cervical ganglion, and hippocampus. The widely used Kv channel blockers, including tetraethylammonium, alpha-dendrotoxin, phrixotoxin-2, and BDS-I, do not mimic or alter the effect of 4-AP on HVACCs. In HEK293 cells expressing various combinations of N-type (Cav2.2) channel subunits, 4-AP potentiates Ca2+ currents primarily through the intracellular beta3 subunit. In contrast, 4-AP has no effect on Cav3.2 channels expressed in HEK293 cells. Furthermore, blocking Kv channels does not mimic or change the potentiating effects of 4-AP on neurotransmitter release from sensory and motor nerve terminals. Thus, our findings challenge the conventional view that 4-AP facilitates synaptic and neuromuscular transmission by blocking Kv channels. Aminopyridines can directly target HVACCs to potentiate neurotransmitter release independent of Kv channels.
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