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

Zizhen Wu, De Pei Li, Shao Rui Chen, Hui Lin Pan

Research output: Contribution to journalArticle

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

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Aminopyridines
4-Aminopyridine
Calcium Channels
Synaptic Transmission
Electric potential
HEK293 Cells
Neurons
Neurotransmitter Agents
Superior Cervical Ganglion
Tetraethylammonium
Myasthenia Gravis
Spinal Ganglia
Spinal Cord Injuries
Multiple Sclerosis
Rats
Hippocampus
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel β subunit. / Wu, Zizhen; Li, De Pei; Chen, Shao Rui; Pan, Hui Lin.

In: Journal of Biological Chemistry, Vol. 284, No. 52, 25.12.2009, p. 36453-36461.

Research output: Contribution to journalArticle

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