COBRE: UVM MED PROJ 3: KINASE & CYTOSKELETAL REGULATION OF POTASSIUM CHANNELS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nerve and muscle cells can be thought of as "electrical cells". Their function depends almost entirely upon their ability to rapidly change the electrical potential across their plasma membrane. Ion channels are the major class of proteins that control such cellular electrical activity. The focus of my lab's research is to understand the mechanisms used by the cell to control Kv1 family potassium ion channels. Using a combination of electrophysiological, biochemical, molecular biological and microscopy techniques, we have discovered a number of unique cellular mechanisms for the regulation of Kv1 family channels involving tyrosine phosphorylation and changes in protein trafficking. Interestingly, although many of the Kv1 family members are sensitive to this type of regulation, the molecular details can be strikingly different between channel sub-types. This is important because in most cells a single ion channel is made up not of only one type of Kv1 protein but of multiple different types. We have found that new regulatory sensitivities emerge from such combinatorial channels that are not predicted by the individual sub-types. One area where this is particularly relevant is in the regulation of Kv1 channels expressed in cerebral artery vascular smooth muscle cells. We have found that Kv1 channel regulation in these cells may be a key contributor to a type of blood vessel constriction that leads to severe brain deficits and death in most patients. Thus, our work bridges the gap between the fundamental cell biology of ion channel regulation and the implications that such regulation has in a serious human pathology. Our major goal over the next year is to use model cell systems to develop greater depth in our understanding of the fundamental cell biological processes involved and to then use those findings to illuminate the mechanisms of ion channel regulation in normal tissue vs. pathological tissue.