Genetic analysis of nicotinic signaling in worms and flies

The nicotinic acetylcholine receptor is among the most thoroughly characterized molecules in the nervous system, and its role in mediating fast cholinergic neurotransmission has been broadly conserved in both vertebrates and invertebrates. However, the accessory molecules that facilitate or regulate nicotinic signaling remain mostly unknown. One approach to identify such molecules is to use molecular genetics in a simple, experimentally accessible organism to identify genes required for nicotinic signaling and to determine the molecular identity of the mutant genes through molecular cloning. Because cellular signaling pathways are often highly conserved between different animal phyla, the information gained from studies of simple organisms has historically provided many critical insights into more complex organisms, including humans. Genetic screens essentially make no prior assumptions about the types of molecules involved in the process being studied; thus, they are well suited for identifying previously unknown components of cell signaling pathways. The sophisticated genetic tools available in organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster have also proven extremely powerful in elucidating complex biologic pathways in the absence of prior biochemical information and for assessing a molecule's in vivo function of in the context of an intact nervous system. This review describes how genetic analysis has been used to investigate nicotinic signaling mechanisms in worms and flies, and the prospects for using these studies to gain insight into nicotinic receptor function and regulation in humans.