The nicotinic acetylcholine receptor (nAChR) is phosphorylated by second messenger-dependent protein kinases, i.e. cAMP-dependent protein kinase and phospholipid and calcium-dependent protein kinase C. The goal of this project is to determine which neuromodulators that are co-relaeased with ACh at the nicotinic synapse activate these kinases. Receptor phosphorylation by these neuromodulators will then be correlated with alterations in receptor function induced by the same neuromodulator. Biochemical and electrophysiological techniques will be used to determine (1) which neuromodulators generate second messengers in Torpedo postsynaptic membranes, (2) which neuromodulators alter nAChR function in muscle cells in culture, (3) what are the sites of phsophorylation on the nAChR which correlate with alterations in its function. Various neurologic and metabolic diseases appear to be disorders of singnal transduction. Once the molecular mechanisms underlying signal transduction in these experimental models are understood, such studies can be extended to more complicated systems. Eventually, knowledge from such studies can be appled to the treatment of diseases involving abnormal signal transduction.
| Pitchford, S; Day, J W; Gordon, A et al. (1992) Nicotinic acetylcholine receptor desensitization is regulated by activation-induced extracellular adenosine accumulation. J Neurosci 12:4540-4 |
