The long term objective of this work is to understand, at a molecular and biophysical level, how RNA editing regulates ion channels and transporters. RNA editing by adenosine deamination is a posttranscriptional process that is essential for proper nervous system function. Although many mRNA substrates have been shown to be edited by this mechanism, very little is known about the functional consequences of these modifications. This proposal focuses on the Na/K pump as a model membrane protein because it plays a central role in the regulation of ion homeostasis. The enzymatic conversion of adenosine to inosine (A -> I) in pre- mRNAs allows multiple protein products from a single gene, thereby extending the genomic capability of an organism. These conversions are not random, but are targeted to functionally important domains within the protein. For example, in the GluRB subunit of the glutamate-gated ion channel, important for fast excitatory synaptic transmission in the central nervous system, editing underlies the conversion of Q to R in the channel's pore. This change, which is essential for survival, renders the receptor impermeable to calcium ions. Edited substrates are identified by comparing genomic and cDNA sequences for the same gene. This process is greatly simplified in squid where editing is extensive. This proposal takes advantage of high level editing in squid to identify mutations that are functionally relevant.
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