Abstract
ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATP inhibitors have been prescribed for diabetes and KATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity.
SIGNIFICANCE STATEMENT ATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATP channels are important drug targets. Both KATP inhibitors (insulin secretagogues) and KATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATP structural pharmacology.
Footnotes
- Received May 31, 2022.
- Accepted August 29, 2022.
The work is supported by grants from the National Natural Science Foundation of China [Grant 91957201], [Grant 31870833], and [Grant 31821091] (to L.C.) and Center for Life Sciences.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
↵1 J.-X.W. and D.D. contributed equally to this work.
- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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