Role of Palmitolyation on Neuronal Estrogen and Androgen Receptor Function

Estrogen receptors were originally characterized as intracellular receptors, acting only in brain regions that regulate reproductive behaviors. Recent discoveries have identified that various neurons throughout the nervous system exhibit responses to estradiol through the activation of surface membrane receptors. These membrane estrogen receptors are now known to lead to alterations in learning and memory, sexual receptivity, motor control and pain. The nervous system is not unique in this regard, as membrane estrogen receptors affect the reproductive organs, the cardiovascular system and bone. The goal of this project is to determine how estrogen receptors are adapted to act as surface membrane signaling molecules. The project willl test the hypothesis that palmitoylation of the estrogen receptor is the essential regulatory step in converting intracellular receptors into membrane signaling proteins. There are 23 different enzymes known to palmitoylate proteins. The principal goal is to identify which of the 23 enzymes is responsible for estrogen receptor palmitoylation, and then to determine the physiological and behavioral impact of manipulating estrogen receptor palmitoylation within brain. Identifying the proteins that palmitoylate steroid receptors provides an innovative experimental system that will challenge dogma and train personnel to integrate various in vivo and in vitro model systems. State-of-the-art cellular/molecular methods will be integrated with established behavioral approaches. Using specific assessment tools, Dr. Mermelstein will monitor the technical, intellectual and instructional development of his trainees. Dr. Mermelstein and his students will also participate in multiple outreach activities, including the development of a Neuroscience Minor as part of the undergraduate curriculum at the University of Minnesota.