Control Mechanisms of Human Voltage Gated Proton Channels, hHv1

Project Summary/Abstract The voltage gated proton channel (HV1) exists in many human tissues and plays numerous roles vital to human health. For example, it contributes to bacterial killing by white blood cells, sperm maturation and mobility, histamine release by basophils, B lymphocyte signaling, and airway fluid regulation. Abnormal HV1 function has been implicated in breast cancer metastasis, brain damage in ischemic stroke, and exacerbation of chronic lymphocytic leukemia. As its gene was not reported until 2006, HV1 is a newcomer to the voltage gated ion channel family. Its structure is unique in resembling a crucial component of all voltage-gated ion channels, namely the voltage-sensing domain that detects membrane potential and transduces this into channel opening or closing. Its newcomer status, unique structure, and essential roles in human health and disease make understanding HV1 function and dysfunction highly significant. The DeCoursey lab has been deeply involved in the study of HV1, from discovering its existence in mammalian and human cells, to identifying its role in a number of human cells and tissues, to finally dissecting the molecule itself to identify which parts perform the major functions. Over the next five years we intend to expand our knowledge of this important molecule at multiple levels, building on our recent progress. Structure-function knowledge is crucial both for understanding mechanisms and for drug design. Much has been learned about structure-function relationships from mutations to the human channel. We believe that it will be more productive in the future to explore structure-function relationships in the highly variable naturally-occurring HV1 in diverse species. An exciting new direction will be studying the involvement of cholesterol and membrane lipid “rafts” in the physiological regulation of hHV1 function. Another focus will be to determine the relationship between hHV1 mutations in B lymphocyte malignancies.