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First published on March 16, 2007; DOI: 10.1124/mol.106.030528

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Received for publication September 6, 2006.
Revised March 15, 2007.
Accepted for publication March 16, 2007.

Subunit-Stoichiometric Evidence for Kir6.2 Channel Gating, ATP Binding and Binding-Gating Coupling

Runping Wang 1, Xiaoli Zhang 1, Ningren Cui 1, Jianping Wu 1, Hailan Piao 1, Xueren Wang 1, Junda Su 1, Chun Jiang 2*

1 GSU 2 Georgia State University

* Address correspondence to: E-mail: cjiang{at}gsu.edu

Abstract

ATP-sensitive K+ channels are gated by intracellular ATP allowing them to couple intermediary metabolism to cellular excitability, whereas the gating mechanism remains unclear. To understand subunit stoichiometry for the ATP-dependent channel gating, we constructed tandem-multimeric Kir6.2 channels by selective disruption of the binding or gating mechanism in certain subunits. Stepwise disruptions of channel gating caused graded losses in ATP sensitivity and increases in basal Popen with no effect on maximum ATP inhibition. Prevention of ATP-binding lowered the ATP sensitivity and maximum inhibition without affecting basal Popen. The ATP-dependent gating required a minimum of two functional subunits. Two adjacent subunits are more favorable for ATP-binding than two diagonal ones. Subunits showed negative cooperativity in ATP binding and positive cooperativity in channel gating. Joint disruptions of the binding and gating mechanisms in the same or alternate subunits of a concatemer revealed that both intra- and inter-subunit couplings contributed to channel gating, although the binding-gating coupling preferred the intra-subunit to inter-subunit configuration within the C terminus. No such preference was found between the C and N termini. These phenomena are well described with the operational model used widely for ligand-receptor interactions.


Key words: Adenosine, Ion channel regulation, Potassium, Desensitization/uncoupling, Phosphorylation/Dephosphorylation, Structure determinations, Thermodynamic and kinetic processes and modeling, Homology modeling of signal transduction families, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches


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