Ionic mechanism of 4-aminopyridine action on leech neuropile glial cells.
Extracellular 4-aminopyridine (4-AP), tetraethylammonium chloride (TEA) and quinine depolarized the neuropile glial cell membrane and decreased its input resistance. As 4-AP induced the most pronounced effects, we focused on the action of 4-AP and clarified the ionic mechanisms involved. 4-AP did not only block glial K+ channels, but also induced Na+ and Ca2+ influx via other than voltage-gated channels. The reversal potential of the 4-AP-induced current was -5 mV. Application of 5 mM Ni2+ or 0.1 mM d-tubocurarine reduced the 4-AP-induced depolarization and the associated decrease in input resistance. We therefore suggest that 4-AP mediates neuronal acetylcholine release, apparently by a presynaptic mechanism. Activation of glial nicotinic acetylcholine receptors contributes to the depolarization, the decrease in input resistance, and the 4-AP-induced inward current. Furthermore, the 4-AP-induced depolarization activates additional voltage-sensitive K+ and Cl- channels and 4-AP-induced Ca2+ influx could activate Ca2+-sensitive K+ and Cl- channels. Together these effects compensate and even exceed the 4-AP-mediated reduction in K+ conductance. Therefore, the 4-AP-induced depolarization was paralleled by a decreasing input resistance.
Müller
M
M
Institut für Neurobiologie, Heinrich-Heine-Universität Düsseldorf, Universitätstrasse 1, D-40225, Düsseldorf, Germany. mmueller@duke.edu
Dierkes
P W
PW
Schlue
W R
WR
D015761:4-Aminopyridine / Q000494:pharmacology*; D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007865:Leeches; D008564:Membrane Potentials / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009457:Neuroglia / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D019581:Neuropil / Q000166:cytology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011803:Quinine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology
D002712:Chlorides; D018691:Excitatory Amino Acid Antagonists; D009125:Muscle Relaxants, Central; D018733:Nicotinic Antagonists; D015221:Potassium Channels; D011810:Quinoxalines; C056723:FG 9041; D019789:Tetraethylammonium; D012964:Sodium; D011803:Quinine; D015761:4-Aminopyridine; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium; D014403:Tubocurarine