Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel β subunit

Zi Zhen Wu, De Pei Li, Shao Rui Chen, Hui Lin Pan

Research output: Contribution to journalArticlepeer-review

Abstract

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 analogs directly stimulate high voltage-activated Ca2+ channels (HVACCs) in acutely dissociated neurons. 4-AP, 4-(aminomethyl) pyridine, 4-(methylamino)pyridine, and 4-di(methylamino) pyridine profoundly increased 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, α-dendrotoxin, phrixotoxin-2, and BDS-I, did 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 potentiated Ca2+ currents primarily through the intracellular β3 subunit. In contrast, 4-AP had no effect on Cav3.2 channels expressed in HEK293 cells. Furthermore, blocking Kv channels did 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 presynaptic HVACCs to potentiate neurotransmitter release independent of Kv channels.

Original languageEnglish (US)
Pages (from-to)36453-36461
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
StatePublished - Dec 25 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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