Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit.
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.
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Zi-Zhen
ZZ
Wu
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
De-Pei
DP
Li
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Shao-Rui
SR
Chen
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77225. Electronic address: huilinpan@mdanderson.org.
Hui-Lin
HL
Pan
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism; D009157:Myasthenia Gravis / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
C500545:CACNA1B protein, human; C479952:CACNA1H protein, human; C503279:Cacna1b protein, rat; C509958:Cacna1h protein, rat; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D002118:Calcium