4-Chloro-m-cresol, an activator of ryanodine receptors, inhibits voltage-gated K(+) channels at the rat calyx of Held.
4-Chloro-m-cresol (4-CmC) is thought to be a specific activator of ryanodine receptors (RyRs). Using this compound, we examined whether the RyR-mediated Ca(2+) release is involved in transmitter release at the rat calyx of Held synapse in brainstem slices. Bath application of 4-CmC caused a dramatic increase in the amplitude of excitatory postsynaptic currents (TIFCs) with the half-maximal effective concentration of 0.12 mm. By making direct patch-clamp whole-cell recordings from presynaptic terminals, we investigated the mechanism by which 4-CmC facilitates transmitter release. 4-CmC markedly prolonged the duration of action potentials, with little effect on their rise time kinetics. In voltage-clamp recordings, 4-CmC inhibited voltage-gated presynaptic K(+) currents (I(pK)) by 53% (at +20 mV) but had no effect on voltage-gated presynaptic Ca(2+) currents (I(pCa)). In simultaneous pre- and postsynaptic recordings, 4-CmC had no effect on the TIFC evoked by I(pCa). Although immunocytochemical study of the calyceal terminals showed immunoreactivity to type 3 RyRs, ryanodine (0.02 mm) had no effect on the 4-CmC-induced TIFC potentiation. We conclude that the facilitatory effect of 4-CmC on nerve-evoked transmitter release is mediated by its inhibitory effect on I(pK).
Suzuki
Daisuke
D
Department of Neurophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Hori
Tetsuya
T
Saitoh
Naoto
N
Takahashi
Tomoyuki
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*
D002120:Calcium Channel Agonists; D003408:Cresols; D024642:Potassium Channels, Voltage-Gated; D017661:Receptors, Presynaptic; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol