Potency of agonists and competitive antagonists on adult- and fetal-type nicotinic acetylcholine receptors.
1. The potency of agonists and competitive antagonists on the two expressed forms of the nicotinic acetylcholine receptor (adult or junctional subtype, epsilon-AChR; fetal or extrajunctional subtype, gamma-AChR) have not previously been compared systematically in homogeneous receptor preparations. 2. Each subtype of the receptor was expressed separately in Xenopus oocytes by cytoplasmic injection of combinations of RNA transcribed in vitro. The presence of each type of receptor was confirmed by single-channel recordings. Expressing oocytes were assayed using discontinuous, single-electrode voltage clamp by measuring peak currents in response to test compounds. 3. The extrajunctional subtype was more potently activated by the nicotinic agonist dimethylphenyl piperazinium iodide (DMPP) than was the junctional form. There was no statistically significant difference in potency between the two subtypes for other nicotinic agonists (nicotine, cytisine and succinylcholine). The rank order of potency for epsilon-AChR was succinylcholine > cytisine > DMPP > nicotine, and that for gamma-AChR was DMPP > cytisine > succinylcholine > nicotine. 4. Two agonists (cytisine and succinylcholine) displayed six- to eight-fold greater intrinsic activity in activating epsilon-AChR over gamma-AChR. There was no difference between the two forms of receptor in efficacy for nicotine. 5. The extrajunctional form was much more potently inhibited by the steroidal competitive antagonist pancuronium than was the junctional receptor. However, there was no significant difference in potency of inhibition by the curariform drug atracurium. 6. Contrary to previous reports, there is no consistent relation between the effect of agonists and antagonists and the subtype of receptor. These data suggest that the resistance or sensitivity to these agents seen in various clinical settings are related to other cellular factors.
Yost
C S
CS
Department of Anesthesia, University of California, San Francisco 94143-0648, USA.
Winegar
B D
BD
D000818:Animals; D005260:Female; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013390:Succinylcholine / Q000494:pharmacology; D014982:Xenopus laevis
D009125:Muscle Relaxants, Central; D009467:Neuromuscular Depolarizing Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D013390:Succinylcholine