?-Subunits co-determine the sensitivity of rat neuronal nicotinic receptors to antagonists

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Abstract
We have investigated the effect of 4 ganglionic cholinergic antagonists (hexamethonium, mecamylamine, pentolinium, trimetaphan) on rat α3β2 and α3β4 neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes. Current responses were elicited by fast application of acetylcholine on voltage-clamped oocytes (holding potential Vinh = -80mV). Concentration-inhibition curves were used to get estimates of IC50, the antagonist concentration yielding 50% reduction of the peak current. The KB's of the antagonists were calculated using estimates of the apparent KD of acetylcholine. The order of affinity of the antagonists was similar for both receptor subtypes: mecamylamine ≈ pentolinium > hexamethonium > trimetaphan. However, α3β4 neuronal nAChRs were 9 to 22 times more sensitive to each of the 4 antagonists than α3β2 receptors. These results further underline the importance of the β -subunit as co-determinant of the functional properties of neuronal nAChRs.