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¹ Department of Medicine (Cardiology), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095
² Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095

Correspondence to James N. Weiss: jweiss{at}mednet.ucla.edu

Phosphatidylinosital-4,5-bisphosphate (PIP₂) acts as an essential factor regulating the activity of all Kir channels. In most Kir members, the dependence on PIP₂ is modulated by other factors, such as protein kinases (in Kir1), G_ß (in Kir3), and the sulfonylurea receptor (in Kir6). So far, however, no regulator has been identified in Kir2 channels. Here we show that polyamines, which cause inward rectification by selectively blocking outward current, also regulate the interaction of PIP₂ with Kir2.1 channels to maintain channel availability. Using spermine and diamines as polyamine analogs, we demonstrate that both spontaneous and PIP₂ antibody–induced rundown of Kir2.1 channels in excised inside-out patches was markedly slowed by long polyamines; in contrast, polyamines with shorter chain length were ineffective. In K188Q mutant channels, which have a low PIP₂ affinity, application PIP₂ (10 µM) was unable to activate channel activity in the absence of polyamines, but markedly activated channels in the presence of long diamines. Using neomycin as a measure of PIP₂ affinity, we found that long polyamines were capable of strengthening either the wild type or K188Q channels' interaction with PIP₂. The negatively charged D172 residue inside the transmembrane pore region was critical for the shift of channel–PIP₂ binding affinity by long polyamines. Sustained pore block by polyamines was neither sufficient nor necessary for this effect. We conclude that long polyamines serve a dual role as both blockers and coactivators (with PIP₂) of Kir2.1 channels.

Abbreviations used in this paper: DA10, 1,10-decanediamine; DA12, 1,12-dodecanediamine; PIP₂, phosphatidylinosital-4,5-bisphosphate.

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