Multifaceted Regulation of Potassium-Ion Channels by Graphen
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2021-12-10 20:34
Graphene quantum dots (GQDs) are an important subfamily of carbon nanomaterials with exceptional photoelectronic properties for which they are known, in particular photoluminescence properties caused by quantum bonding and edge effects, and are widely used for cell and tissue imaging. In addition, GQDs are of great interest due to their excellent chemical stability, ease of fabrication and low biotoxicity. Potassium ion channels are the most diverse and widely used type of ion channels. They are found in almost all cells, from prokaryotes and archaea to complex polybiotic eukaryotes.
Potassium channels are a superfamily of membrane protein machines with multiple subunits that open and close (gate) in a coordinated manner to conduct potassium ions down their electrochemical gradient under physiological conditions, usually from the intracellular to the extracellular space. In excitable cells, regulated potassium ion flux determines the resting membrane potential and influences cellular excitability, including the duration and frequency of action potentials. The potassium channel superfamily is divided into five subfamilies with distinct membrane topologies and different gating stimuli. A team led by Professor Ruhong Zhou, Director of the Centre for Quantitative Biology at Zhejiang University and Director of the Shanghai Institute for Advanced Studies, recently published an article in the ACS Journal of Applied Materials and Interfaces detailing the effects of GQD on three major potassium channel proteins, including Kir3.2, Kv1.2, and K2P2, using a combination of theoretical simulations and electrophysiological experiments.
We used a combination of theoretical simulations and electrophysiological experiments to explore the effects of GQD on the biological functions of three major potassium channel proteins, including Kir3.2, Kv1.2 and K2P2, and to investigate in detail the molecular mechanisms involved. Using molecular dynamics simulations, we found that GQD can form small clusters and bind to the extra-membrane channel port of Kir3.2, blocking the channel port, which inhibits the flux of potassium ions in the channel and ultimately affects the biological activity of the channel. IC50 is found at 0.55ug/ml. At the same time, we also found the exact opposite phenomenon in the Kv1.2 channel, namely that GQD activates the Kv1.2 potassium channel protein. Molecular dynamics simulations showed that this activation occurs mainly through the binding of GQD to channel-related gating domains, in particular to several positively charged key amino acids associated with gating. This blocks the closure of the relevant gating and ultimately increases the potassium permeability of the channel; electrophysiological experiments showed that GQD activates Kv1.2 with an EC50 of about 0.08 ug/ml.
We combined theoretical simulations and electrophysiological experiments to fully demonstrate that GQD has multiple potassium-regulating behaviours. These studies represent a pioneering theoretical exploration and a foundation for future development of appropriate nanomedicines.
The first author is Dr. Zonglin Gu, co-first author is Austin M. Baggetta from Northeastern University, and co-corresponding authors are Associate Professor Xuanyu Meng from the State Key Laboratory of Radiation Medicine and Protection, Soochow University, Associate Professor Leigh D. Plant from the Department of Pharmacy, Northeastern University, and Professor Ruhong Zhou.
The publication is available at https://pubs.acs.org/doi/10.1021/acsami.1c01569
