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(Circulation Research. 2002;90:554.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Intramolecular Interaction of SUR2 Subtypes for Intracellular ADP-Induced Differential Control of K_ATP Channels

Kenji Matsushita, Kengo Kinoshita, Tetsuro Matsuoka, Akikazu Fujita, Takashi Fujikado, Yasuo Tano, Haruki Nakamura, Yoshihisa Kurachi

From the Departments of Pharmacology II (K.M., T.M., A.F., Y.K.) and Ophthalmology (K.M., T.F., Y.T.), Graduate School of Medicine, and the Research Center For Structural Biology (H.N.), Institute for Protein Research, Osaka University, Suita, Osaka, Japan; and the Division of Science of Biological Supramolecular Systems (K.K.), Graduate School of Integrated Science, Yokohama University, Yokohama, Kanagawa, Japan.

Correspondence to Y. Kurachi, Dept of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail ykurachi{at}pharma2.med.osaka-u.ac.jp

ATP-sensitive K⁺ (K_ATP) channels are composed of sulfonylurea receptors (SURs) and inwardly rectifying Kir6.2-channels. The C-terminal 42 amino acid residues (C42) of SURs are responsible for ADP-induced differential activation of K_ATP channels in SUR-subtypes. By examining ADP-effect on K_ATP channels containing various chimeras of SUR2A and SUR2B, we identified a segment of 7 residues at central portion of C42 critical for this phenomenon. A 3-D structure model of the region containing the second nucleotide-binding domain (NBD2) of SUR and C42 was developed based on the structure of HisP, a nucleotide-binding protein forming the bacterial Histidine transporter complex. In the model, the polar and charged residues in the critical segment located within a distance that allows their electrostatic interaction with Arg1344 at the Walker-A loop of NBD2. Therefore, the interaction might be involved in the control of ADP-induced differential activation of SUR2-subtype K_ATP channels.

Key Words: homology modeling • K_ATP channel • nucleotide binding domain • sulfonylurea receptor • Walker motif

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