BETA-SUBUNITS CO-DETERMINE THE SENSITIVITY OF RAT NEURONAL NICOTINIC RECEPTORS TO ANTAGONISTS

We have investigated the effect of 4 ganglionic cholinergic antagonists (hexamethonium, mecamylamine, pentolinium, trimetaphan) on rat alpha 3 beta 2 and alpha 3 beta 4 neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes. Current responses were elicited by fast application of acetylcholine on voltage-clamped oocytes (holding potentialV(h) = -80m V). Concentration-inhibition curves were used to get estimates of IC50, the antagonist concentration yielding 50% reduction of the peak current. The K-B's of the antagonists were calculated using estimates of the apparent K-D of acetylcholine. The order of affinity of the antagonists was similar for both receptor subtypes: mecamylamine approximate to pentolinium > hexamethonium> trimetaphan. However, alpha 3 beta 4 neuronal nAChRs were 9 to 22 times more sensitive to each of the 4 antagonists than alpha 3 beta 2 receptors. These results further underline the importance of the beta-subunit as co-determinant of the functional properties of neuronal nAChRs.