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

J Biol Chem. 2009 Dec 25;284(52):36453-36461. doi: 10.1074/jbc.M109.075523. Epub 2009 Oct 22.

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 Ca(2+) 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, alpha-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 Ca(2+) currents primarily through the intracellular beta(3) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology*
  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / metabolism*
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Ganglia, Spinal / metabolism
  • Humans
  • Male
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / metabolism
  • Myasthenia Gravis / genetics
  • Myasthenia Gravis / metabolism
  • Neuromuscular Junction / metabolism*
  • Neurons / metabolism
  • Potassium Channel Blockers / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord Injuries / genetics
  • Spinal Cord Injuries / metabolism
  • Synaptic Transmission / drug effects*

Substances

  • CACNA1B protein, human
  • CACNA1H protein, human
  • Cacna1b protein, rat
  • Cacna1h protein, rat
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Calcium Channels, T-Type
  • Potassium Channel Blockers
  • 4-Aminopyridine
  • Calcium