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Department of
Biochemistry Ph.D. - The Johns Hopkins University, 1986 Associate Professor Current Research: Our laboratory's research is focused on the endoplasmic reticulum (ER), an intracellular organelle that plays a key role in many cellular processes, including protein synthesis and calcium signaling. We are particularly interested in the molecular components of the ER that provide pathways for the complex, bidirectional traffic of molecules ranging in size from ions to proteins between the lumen of the ER and the cytosol. This traffic is essential for the synthetic and signaling functions of the ER, and changes in the cellular environment that affect this traffic might contribute to the etiology of degenerative diseases (e.g., Alzheimer's disease) or the injury produced by acute trauma (e.g., ischemia). We propose that ribosome-bound translocons (referred to as RBTs) in the ER might be an important, but previously unstudied, pathway for signals between the ER and cytosol. The role of RBTs in mediating the co-translational translocation of nascent protein chains across the ER membrane is firmly established, and this role was recently expanded to include the export of proteins destined for degradation in the cytosol. However, a broader role of translocons in membrane transport has been overlooked, even though the pore of an RBT is large enough that it could be permeable to a variety of small molecules, including Ca. We recently demonstrated that a polar solute, 4-methylumbelliferyl-alpha-D-glucopyranoside (4MG ), can permeate RBTs when the pore is not occupied by a nascent polypeptide chain. This is not simply an experimental curiosity, because we also observed a large basal entry of 4MG through translationally-inactive, but ribosome-bound translocons. The significance of this basal permeability is underscored by recent reports that the majority of translocons remain in a ribosome-bound state following the normal termination of translation and release of nascent proteins, i.e., this pathway may be persistently active. We have also reported that the permeability of the RER can be dynamically coupled to protein synthesis. When the rate of translation at the RER is high, more RBTs are blocked by nascent proteins, whereas when the rate of translation is low, the permeability is high because few RBTs are blocked by nascent proteins. This observation is highly relevant to the response of cells to stress, in which a ubiquitous response is the transient and global inhibition of protein translation. We predict that an increased permeability or "leakiness" of the RER might be a common response in stressed cells. Finally, we also have reported that unoccupied RBTs can release calcium from the ER, and it might represent a third type of calcium release channel in the ER. As we continue to study how the pore of RBTs might convey signals between the ER and cytosol, we are focusing on the role of RBTs in calcium signaling, the responses of cells to stress, and the selectivity of the pore of RBTs for various molecules. Other Recent Projects: We have also recently studied (1) the role of ATP-sensitive K channels in regulating the progression of breast cancer cells through the G1 phase of the cell cycle; and (2) the transport vesicles that deliver voltage-gated ion channels to the plasma membrane. References:
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