Determination of the minimal structure of RNA polymers that prevent inhibition of the nicotinic acetylcholine receptor by cocaine


Kannan Sivaprakasam, Oné R. Pagan, and George P. Hess. Department of Molecular Biology and Genetics, Cornell University, 217 Biotechnology Building, Ithaca, NY 14853-2703
Nicotinic acetylcholine receptor (nAChR) is a member of membrane proteins that control signal transmission between cells in the nervous system. Transient kinetic investigations of the inhibition mechanism of the nAChR in BC3H1 cells indicated that inhibitors bind with higher affinity to an allosteric site on the closed-channel form of the nAChR and thereby decrease the channel-opening equilibrium constant. This conclusion indicated that compounds may be found that bind with equal affinity to this allosteric site on the open- and closed-channel forms and, therefore, do not change the channel-opening equilibrium constant, but can displace inhibitors. Combinatorially synthesized RNA ligands containing 90 nucleotides were found that had this property. We now report that only 9 nucleotides containing the consensus sequence of GCUGAA are required. Further investigation of these molecules are in progress to determine if their structure can lead to the design of small organic molecules that can counteract cocaine inhibition.