The α7 Nicotinic Acetylcholine Receptor Complex: One, Two or Multiple Drug Targets?

The alpha 7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of diseases ranging from schizophrenia and Alzheimer's disease to chronic pain and inflammatory diseases. Focusing on the central nervous system, we describe how endogenous and experimental compounds and proteins regulate expression and function of the alpha 7 nAChR. Drug development efforts have hitherto focused on direct manipulation of the alpha 7 nAChR, but it is still not clear, whether agonism/antagonism or allosteric modulation is preferable as a potential drug therapy. In addition, the action of such compounds in vivo is highly dependent on alpha 7 nAChR-interacting proteins, such as RIC-3 and lynx1, which modulate expression and function of the receptor. These regulatory proteins are often not expressed in in vitro models used to study alpha 7 nAChR function, and it is not known to what extent they are involved in diseases such as schizophrenia and Alzheimer's disease. Furthermore, alpha 7 nAChR agonists and allosteric modulators differentially alter expression and functionality of the alpha 7 nAChR with repeated administration, which suggests that there may be fundamentally different outcomes of long-term administration with these different types of compounds. Finally, we describe the special case of A beta(1-42) binding to the alpha 7 nAChR, which may pose a unique challenge to drug development of alpha 7 nAChR-specific ligands for Alzheimer's disease. Hopefully, a greater knowledge of the many factors influencing alpha 7 nAChR function as well as an increasing pipeline of specific drug candidates, enabling a more subtle manipulation of alpha 7 nAChR function, may facilitate alpha 7 nAChR drug development efforts.