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Biophys J, October 1998, p. 1817-1827, Vol. 75, No. 4

Epibatidine Activates Muscle Acetylcholine Receptors with Unique Site Selectivity

Richard J. Prince and Steven M. Sine

Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905 USA

We recently showed that at desensitized muscle nicotinic receptors, epibatidine selects by 300-fold between the two agonist binding sites. To determine whether receptors in the resting, activatible state show similar site selectivity, we studied epibatidine-induced activation of mouse fetal and adult receptors expressed in 293 HEK cells. Kinetic analysis of single-channel currents reveals that (-)-epibatidine binds with 15-fold selectivity to sites of adult receptors and 75-fold selectivity to sites of fetal receptors. For each receptor subtype, site selectivity arises solely from different rates of epibatidine dissociation from the two sites. To determine the structural basis for epibatidine selectivity, we introduced mutations into either the gamma  or the delta  subunit and measured epibatidine binding and epibatidine-induced single-channel currents. Complexes formed by alpha  and mutant gamma (K34S+F172I) subunits bind epibatidine with increased affinity compared to alpha gamma complexes, whereas the kinetics of alpha 2beta delta gamma (K34S+F172I) receptors reveal no change in affinity of the low-affinity site, but increased affinity of the high-affinity site. Conversely, complexes formed by alpha  and mutant delta (S36K+I178F) subunits bind epibatidine with decreased affinity compared to alpha delta complexes, whereas the kinetics of alpha 2beta gamma delta (S36K+I178F) and alpha 2beta epsilon delta (S36K+I178F) receptors show markedly reduced sensitivity to epibatidine. The overall data show that epibatidine activates muscle receptors by binding with high affinity to alpha gamma and alpha epsilon sites, but with low affinity to the alpha delta site.

Biophys J, October 1998, p. 1817-1827, Vol. 75, No. 4
© 1998 by the Biophysical Society   0006-3495/98/10/1817/11  $2.00


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