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.
Wu
Zi-Zhen
ZZ
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Li
De-Pei
DP
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Chen
Shao-Rui
SR
Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Pan
Hui-Lin
HL
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.
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