"The goal of this project is to develop new methods of single-cell imaging and single-molecule microscopy to detect and characterize the regulation of L-type calcium channels by the calcium signaling protein calmodulin. Calcium is an important signal messe nger that can enter cells through calcium channels and is vital for processes including muscle contraction and heartbeat. The project will track interactions between calmodulin and the channel throughout the regulatory sequence and will determine the role of heterogeneity and clustering in their function. The development of new biophysical methods to detect single molecules in single cells is one of the most important challenges in biophysics. The project will combine the expertise of two researchers, one (Harms) experienced with L-type calcium channels and one (Johnson) experienced with calmodulin. Recent developments in the labs of both researchers provide a unique opportunity for a major step forward in single-molecule spectroscopy of protein interactio ns and regulation in cells. Specific objectives of the project are: (1) development of new single-molecule methods to detect calmodulin and calcium channels in cells; (2) determination of the extent of association of calmodulin with channels; and (3) track ing the progression of calmodulin-channel coupling and structure in channel regulation. Prof. Johnson has established a well-published research program in spectroscopy and protein dynamics. Further progress in his research requires training in wide-field microscopy and cell culture. Prof. Harms has established a microscopy lab at Würzburg with expertise in exactly these areas. Prof. Johnson will bring fluorescently labeled calmodulin constructs and expertise in single-molecule spectroscopy of calmodulin. Prof. Harms will bring expertise in fluorescence imaging and electrophysiological measurements of calcium channels. Their collaboration will enable rapid advances and will lead to an ongoing collaboration."
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