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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。神经细胞和肌肉细胞可以被认为是“电细胞”。它们的功能几乎完全取决于它们快速改变质膜电位的能力。离子通道是控制这种细胞电活动的主要蛋白质类别。我实验室的研究重点是了解细胞控制Kv 1家族钾离子通道的机制。使用电生理学，生物化学，分子生物学和显微镜技术相结合，我们已经发现了一些独特的细胞机制，涉及酪氨酸磷酸化和蛋白质运输的变化的Kv 1家族通道的调节。有趣的是，尽管许多Kv 1家族成员对这种类型的调节敏感，但通道亚型之间的分子细节可能存在显著差异。这很重要，因为在大多数细胞中，单个离子通道不仅由一种Kv 1蛋白组成，而且由多种不同类型组成。我们已经发现，新的监管敏感性出现从这样的组合渠道，而不是预测的个别亚型。其中一个特别相关的领域是脑动脉血管平滑肌细胞中表达的Kv 1通道的调节。我们发现，这些细胞中的Kv 1通道调节可能是导致大多数患者严重脑功能缺损和死亡的一种血管收缩的关键因素。因此，我们的工作弥合了离子通道调节的基本细胞生物学与这种调节在严重的人类病理学中的含义之间的差距。我们明年的主要目标是使用模型细胞系统来更深入地了解所涉及的基本细胞生物学过程，然后使用这些发现来阐明正常组织与病理组织中离子通道调节的机制。

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.