When cells are busily firing electrical signals for events like contracting a muscle or regulating blood pressure, they’ve got to open and close intricate channels for potassium and other ions. “Big Potassium” channels, known as BK channels, contain “extra-large pores,” says Jianhan Chen (chemistry, biochemistry and molecular biology), “so they can sustain very large current, which lets the cell respond faster.” BK channels play an important role in many health conditions such as hypertension, epilepsy, autism and mental retardation.
A key puzzle over the past 30 years has been trying to understand how cells close, or gate, BK channels, which have an unusually large central pore. In more typical-sized pores, the channel proteins generally contain structures (“gates”) that move into position to physically close the passage. But findings by others had shown that, inexplicably, the large central pore in BK channels “seems to remain wide open in both activated and deactivated states.” Chen says, “the pore still looks literally wide open even when it is closed to potassium passage. Nobody could understand this.”
"We are really proud of solving one of the biggest mysteries in the BK field.”
Computational biophysicists like Chen are not used to making discoveries, he says, so when he and colleagues cracked the secret of how cells regulate Big Potassium (BK) channels, they thought it must be a computational artifact. But after many simulations and tests, they have indeed identified the BK gating mechanism that had eluded science for many years.
“There were a lot of hypotheses, but no answers,” Chen notes. Now in Nature Communications, his team demonstrates that a physical gate is not required for closing BK channels. Instead, a phenomenon known as “hydrophobic dewetting” gives rise to a vapor phase in the pore’s central cavity to block intracellular access to the selectivity filter.
The gate mechanism in BK channels they have been studying is “drastically different from what has been observed in other ion channels,” the authors point out. “We believe that this work represents a paradigm shift in our thinking of regulation and gating of BK channels,” and is “one of the first few examples of a true ‘hydrophobic gate,’ where the barrier to ion permeation arises directly from dewetting transitions.” When the BK pore is oily, the water forms a vapor phase that acts like a barrier and prevents all ions from entering, Chen says. “Nothing gets through.”
His team used computational modeling and physics-based atomistic simulations supported by the enormous computational power of a GPU cluster at the Massachusetts Green High Performance Computing Cluster in nearby Holyoke to carry out this work. Chen explains, “Our data reconciles key results from previous experimental studies without invoking any crazy ideas. We are really proud of solving one of the biggest mysteries in the BK field.”
He says, “If you think about why nature might want to use a vapor barrier where there is a big pore that has to carry a lot of electrical current, to apply a physical barrier you would need a protein structural re-arrangement which would probably be either too big or too slow, or both. In a way, nature is really clever in using this hydrophobic dewetting phenomenon to create a sensitive and fast gate. We were actually really surprised to see that the changes in pore shape and surface properties are relatively small and subtle, but they have big consequences on its hydration properties.” Further, Chen says, “In principle, that knowledge should be useful in developing new therapies and strategies in targeting the channel.”
Chen is part of UMass Amherst’s chemistry, biochemistry and molecular biology program and a member of the campus’s Institute for Applied Life Sciences, which translates fundamental science into new targets, leads and disease models. First author of their paper, Zhiguang Zhang, is a postdoctoral research fellow in Chen’s lab and second author Mahdieh Yazdani is a graduate student there.
This work is supported by a new four-year, $2.9 million grant recently funded by NIH’s National Heart, Lung, and Blood Institute, to a collaborative team led by Jianmin Cui at Washington University, St. Louis, Chen at UMass Amherst and Xiaoqin Zou at the University of Missouri.