Published October 16, 2013
Scientists in the Department of Physiology and Biophysics are the first to quantify the difference between two subunits of a neuromuscular protein at the molecular level—research that has potential implications for a deadly fetal syndrome.
They found that the fetal subunit of the neuromuscular acetylcholine receptor (AChR) generates nearly 50 percent more energy from the neurotransmitter than its adult counterpart.
Their discovery helps explain not only why this receptor responds to the low concentrations of the neurotransmitter acetylcholine present during gestation, but why a mutation may cause fetal akinesia syndrome.
Anthony Auerbach, PhD, professor of physiology and biophysics, and postdoctoral associate Tapan Nayak, PhD, conducted the research, which was published in the Proceedings of the National Academy of Sciences.
Scientists have long known that the adult and fetal AChR subunits differ; the UB research is the first to explain that distinction in energy units.
“Our motivation was to understand exactly how the adult and fetal subunits are different in terms of the energy that they provide to the operation of the receptor, which is a protein nanomachine,” Auerbach explains.
“We found that the fetal neurotransmitter binding site provides a much bigger energy boost than its adult counterpart,” he says.
“This allows the system to switch on easier and the whole system to operate with a lower concentration of neurotransmitter.”
The energy boost in the AChR fetal subunit allows the nervous system to trigger muscle contractions, which in turn allows the nervous and muscle systems to develop properly.
Conversely, the absence of that boost may cause fetal disease.
If the embryo is missing the fetal subunit, or the subunit is mutated, Auerbach explains, the body tries to substitute an adult subunit. However, the adult subunit can’t respond to the low concentrations of neurotransmitter present during development.
The result is multiple pterygium—a rare and frequently fatal condition characterized by webbing of the skin and at the joints, muscle weakness and joint deformities—or its milder form, Escobar syndrome.
The UB research also has potential implications for nerve injury.
When such injuries occur, the fetal receptor re-expresses itself to regenerate nerves.
“We speculate that this happens because successful regeneration may require that extra boost from the fetal subunit,” Nayak says. “Therefore, the fetal subunit could be a therapeutic target if we can find something that escalates its expression in adults.”
The researchers next plan to study how drugs, including nicotine, and the nutrient choline affect the fetal receptor.
They also plan to find the source of the subunit’s energy boost.
The UB team’s research was made possible by the Auerbach lab’s vast store of information about neuromuscular AChRs—likely the world’s largest database on the protein.
“Our lab has the ability to design and control the behavior of this protein that goes beyond anybody else’s,” Auerbach says. “That’s because we’ve studied it at the level of single molecules and energy, for thousands of mutations.”
“There’s nothing fancy about our techniques,” he adds. “What’s fancy is our analysis—our ability to break down data into modules and to understand a protein in the form of the energies that undergird function.
“That’s extremely powerful.”