Differences in conformational properties of the second intracellular loop (IL2) in 5HT(2C) receptors modified by RNA editing can account for G protein coupling efficiency

Adenosine-to-inosine RNA editing events that have been demonstrated for 5HT (2C) receptors resulted in alterations of the amino acid sequence at positi ons 156, 158 and 160 in the intracellular loop 2 (IL2) region. The edited r eceptor isoforms were shown to have reduced basal activity, but similar max imum responses to agonist binding. To identify the molecular mechanism of t hese pharmacological effects of editing we explored the conformational prop erties of the edited IL2 in comparison with the wild type. The results from conformational studies of the IL2 isoforms, using biased Monte Carlo simul ations with an implicit solvent model based on a screened Coulomb potential , show that the compared loops differ in their preferred spatial orientatio ns as a result of differences in the conformational space that is accessibl e to them by energy criteria. For the IL2 of the unedited (5HT(2C-INI)) rec eptor, the preference for structures oriented towards the 7TM bundle is lar ger than for the 5HT(2C-VGV) edited receptor. This difference in preferred orientation can affect the association of IL2 with other intracellular loop domains involved in G protein coupling and hence the coupling efficiency. The results illustrate the high sensitivity of the system to small changes in the interaction surface presented to other intracellular loops, and/or t he G protein.