POTENCY OF AGONISTS AND COMPETITIVE ANTAGONISTS ON ADULT-TYPE AND FETAL-TYPE NICOTINIC ACETYLCHOLINE-RECEPTORS

1, The potency of agonists and competitive antagonists on the two expr essed forms of the nicotinic acetylcholine receptor (adult or junction al subtype, epsilon-AChR; fetal or extrajunctional subtype, gamma-AChR ) have not previously been compared systematically in homogeneous rece ptor preparations, 2, Each subtype of the receptor was expressed separ ately in Xenopus oocytes by cytoplasmic injection of combinations of R NA transcribed in vitro. The presence of each type of receptor was con firmed by single-channel recordings. Expressing oocytes were assayed u sing discontinuous, single-electrode voltage clamp by measuring peak c urrents in response to test compounds. 3. The extrajunctional subtype was more potently activated by the nicotinic agonist dimethylphenyl pi perazinium iodide (DMPP) than was the junctional form. There was no st atistically 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> cyti sine > DMPP > nicotine, and that for gamma-AChR was DMPP > cytisine > succinylcholine > nicotine, 4. Two agonists (cytisine and succinylchol ine) displayed six- to eight-fold greater intrinsic activity in activa ting epsilon-AChR over gamma-AChR, There was no difference between the two forms of receptor in efficacy for nicotine, 5, The extrajunctiona l form was much more potently inhibited by the steroidal competitive a ntagonist pancuronium than was the junctional receptor. However, there was no significant difference in potency of inhibition by the curarif orm drug atracurium. 6. Contrary to previous reports, there is no cons istent relation between the effect of agonists and antagonists and the subtype of receptor. These data suggest that the resistance or sensit ivity to these agents seen in various clinical settings are related to other cellular factors.