Significance

SIGNIFICANCE

The significance of our studies lies in several areas pertinent to the different functions of nAChRs. First, an example of the importance of the proposed studies is the characterization of the novel lipid-exposed αC418W mutation in Torpedo and muscle-type AChRs (Lee et al., 1994, Lasalde et al., 1996, Ortiz-Miranda et al, 1997; Tamamizu et al., 1999) that predicted that this lipid-exposed mutant was a slow-channel mutation. Very recently a slow-channel congenital myathenic syndrome has been shown to be caused by the same αC418W mutation in humans. We had developed a transgenic model for the αC418W in Collaboration with Dr Christopher Gomez (U. Chicago) two years before this Congenital Myasthenic Syndrome (CMS) was reported, and now a fundamental aspect of the proposed research is to define the mechanism by which this novel lipid-exposed mutant leads to endplate myopathy in humans. Second, these studies will produce the most accurate map of the lipid protein interface of the Torpedo and muscle-type AChRs. Furthermore, we will gain insight into how the structural differences of lipid-exposed domains in these two AChR species are involved in the regulation of the ion channel and functional adaptation to different lipid environments. Third these studies are likely to provide important new information about the functional consequences of interactions of the AChR at the lipid interface and the regulation of AChR function by cholesterol. Such protein-lipid interactions are poorly understood aspects of the functional properties of ligand-gated ion channels. The physiological effects of cholesterol on the AChR function could have paramount implications if we consider that an increment of 12% cholesterol can deplete 40% of the nAChRs in the CNS. For instance, it has been noted that learning deficits in Alzheimer’s disease can be present even before any observable cell loss, suggesting that the initial disruption of cognitive function in this disease is not due to cell death, but rather to the disruption of nAChR receptors and synaptic transmission (O’Neill et al. 2002). Along that line, epidemiological evidence has suggested that high cholesterol is a risk factor for Alzheimer’s Disease (AD); the incidence of AD was found to be greater among individuals with high cholesterol levels (Roher et al., 1999). The cholesterol inhibition of AChR function is a central aspect of our research. Another fundamental goal of this laboratory is to improve the size and quality of ATPase-free Torpedo AChR crystals for X-ray diffraction studies. Fourth, a high-resolution structure of the AChR could provide critical information for developing new nicotinic AChR agonists and new pharmacological therapies to treat neurological disorders such as Alzheimer’s and Parkinson’s diseases. Fifth, an implicit assumption of this research is that principles discovered about the AChR with respect to lipid-protein interactions, dynamics of helix-helix interactions, cholesterol inhibition and dynamics of the lipid protein interface will be relevant to other important receptor systems, ion channels, and membrane proteins.

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