Factors influencing the low-frequency associated nicotinic ACh autoreceptor-mediated depression of ACh release from rat motor nerve terminals.
1. We have studied the inhibitory autoreceptor control of acetylcholine (ACh) release from rat motor nerve endings using an electrophysiological technique to quantify evoked ACh release in isolated hemidiaphragm muscles. Quantal ACh release (m) was estimated from the ratio of amplitudes of nerve evoked endplate currents and spontaneously occurring miniature endplate currents. 2. The nicotinic ACh receptor agonist cytisine (1 microM) decreased m at 0.5 Hz by around 20% but had no effect on m at 50 Hz. Changing the extracellular Ca(2+) concentration from 1.8 mM to either 0.45 or 3.6 mM abolished the effect of cytisine on m at 0.5 Hz. The nicotinic ACh receptor antagonist hexamethonium (200 microM) increased m at 0.5 Hz by 15 - 20%. 3. The effects of cytisine and hexamethonium on m at 0.5 Hz were blocked by 10 microM verapamil, which itself significantly increased m. However, the effects of cytisine and hexamethonium on m at 0.5 Hz were not sensitive to 10 microM of the calmodulin antagonist, W-7. This concentration of W-7 attenuates effects on ACh release mediated by facilitatory prejunctional nicotinic ACh autoreceptors. 4. Our present observations are suggestive of actions of cytisine and hexamethonium to activate and inhibit respectively negative-feedback prejunctional nicotinic ACh autoreceptors. Further, they strengthen the case for the existence of two separate and independent autoregulatory mechanisms for the control of ACh release from motor nerve terminals and give a preliminary insight into the cellular mechanism involved in the autoinhibition of ACh release.
Prior
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Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow G4 0NR, UK. c.b.prior@strath.ac.uk
Singh
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D000109:Acetylcholine / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D001392:Azocines; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003964:Diaphragm / Q000187:drug effects; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D017660:Autoreceptors; D001392:Azocines; D002118:Calcium; D002121:Calcium Channel Blockers; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011807:Quinolizines; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D014700:Verapamil; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C017967:W 7