TY - JOUR
T1 - Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel β subunit
AU - Wu, Zi Zhen
AU - Li, De Pei
AU - Chen, Shao Rui
AU - Pan, Hui Lin
PY - 2009/12/25
Y1 - 2009/12/25
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.075523
DO - 10.1074/jbc.M109.075523
M3 - Article
C2 - 19850918
AN - SCOPUS:73649108583
SN - 0021-9258
VL - 284
SP - 36453
EP - 36461
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -