 Associate Professor
PhD: The Johns Hopkins University
Postdoctoral Training: University of CalgaryJoined the faculty:
WVU: 1991, Biochemistry:
2001
Affiliations:
Center for Cardiovascular and Pulmonary Sciences
Teaching: BMS
705,
CCMD 793L,
PCOL 744,
PCOL 761, PCOL760, PCOL743,
BMS 715
Office: 3148
Lab: 3148
Phone: (304) 293-3159
Fax: (304) 293-6854
Email:
wwonderlin@hsc.wvu.edu |
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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: Woodfork,
K.W., Wonderlin, W.F., Peterson, V.A. & Strobl, J.S.
(1995) Inhibition of ATP-sensitive potassium channels
causes reversible cell-cycle arrest of human breast
cancer cells in tissue culture. J. Cell Physiol.
162:163-171.
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- Wonderlin, W.F.
(2009) Constitutive, translation-independent opening
of the protein-conducting channel in the endoplasmic
reticulum. Pflugers Arch., 457:917-930.
- Murlasits Z, Cutlip
RG, Geronilla KB, Rao KM, Wonderlin WF & Alway SE.
(2006) Resistance training increases heat shock
protein levels in skeletal muscle of young and old
rats. Exp. Gerontol. 41:398-406.
- A. Roy & W.F.
Wonderlin (2003) The Permeability of the Endoplasmic
Reticulum is Dynamically Coupled to Protein
Synthesis. J. Biol. Chem., 278:4397-4403.
- D. Heritage & W.F.
Wonderlin (2001) Translocon Pores in the Endoplasmic
Reticulum are Permeable to a Neutral, Polar
Molecule. J. Biol. Chem., 276:22655-22662.
- E. Klimatcheva &
W.F. Wonderlin (1999) An ATP-Sensitive K+ Current
that Regulates Progression Through Early G1 Phase of
the Cell Cycle in MCF -7 Human Breast Cancer Cells.
J. Membrane Biol., 171:35-46.
- Wonderlin, W.F.
(1998) The rate zonal separation of organelles from
dilute suspensions: The problem of a large sample
volume. Anal. Biochem. 258:74-79.
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Wonderlin Lab
