Allosteric Modulation by dFBr and the Molecular Basis of its Interaction with a Novel Allosteric Binding Site on Nicotinic Acetylcholine Receptors

The neuronal nicotinic acetylcholine receptor (nAChR) is one of the most important ligand-gate ion channel families and includes 16 different receptor subunits. (Gotti and Clementi 2004) Both versatile in function and diverse in composition, nAChRs play a critical role in synaptic transmission and regulate key processes including learning, memory and muscle contraction. (Gotti et al., 2006) Dysfunction and dysregulation of nAChRs are thought to be involved in disorders including Autism, Alzheimers’ and Parkinson’s disease. (Court et al., 2001; Nordberg, 2001). Nicotinic AChRs can be modulated by a large number of drugs, key agonists include nicotine, epibatidine, carbachol, and varenicline. Unfortunately, the use of agonists as therapeutic agents can produce unpredictable effects due to the rapid activation/desensitization kinetics of nAChRs. (Kim et al., 2007, Moroni et al) In recent years there has been substantial interest in alternate approaches to increasing activity of nicotinic receptors through the use of positive allosteric modulators (PAMs). PAMs possess no intrinsic activity, but enhance the activity of receptors when applied in the presents of agonist. (Kim et al., 2007; Weltzin and Schulte, 2010) One such PAM is desformylflustrabromine (dFBr), a tryptophan metabolite of the marine bryozoan flustra foliacea with the ability to potentiate nAChR containing a β2 subunit. (Weltzin and Schulte, 2010). Our previous studies have shown that dFBr can potentiate Ach response by 265% at 3μM through increases in efficacy (German et al, 2007). Inhibition is observed at higher concentration. (Weltzin and Schulte, 2010)