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Molecular Basis of Inward Rectification: Structural Features of the Blocker Defined by Extended Polyamine Analogs

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri (G.L., C.G.N.); and CellGate Inc., Redwood City, California (L.J.M.)

Polyamines cause inward rectification of Kir K⁺ channels by blocking deep within the channel pore. We investigated structural constraints of polyamine block of strongly rectifying mutant K_ATP channels (Kir6.2[L164C,N160D,C166S] + SUR1). We studied three groups of polyamine analogs: 1) conformationally restricted linear tetra-amines with a cycloalkyl or alkene group between the second and third amines (CGC-11047, CGC-11093, CGC-11099, and CGC-11098), 2) conformationally restricted linear deca-amines with a cycloalkyl or alkene group between the fifth and sixth amines (CGC-11150, CGC-11179, and CGC-11241), and 3) cyclic tetra-amines (CGC-11174, CGC-11197, CGC-11199, and CGC-11254). All linear analogs cause a voltage-dependent block similar to that of spermine, but slightly weaker (at 1 µM, V_1/2 for spermine block = -10 ± 1 mV, Z = 2.9 ± 0.1, n = 19; V_1/2 for analogs varies from polyamine -7 to +10 mV, Z = 2.6-3.9). These data indicate tolerance for conformational restriction and an upper limit to the voltage dependence of the blocking process. There was no voltage-dependent block by the cyclic compounds; instead, they induce irreversible rundown of the current. Structural models of Kir channels suggest that a narrow entry at the top of the cytoplasmic pore may exclude cyclic analogs from the inner cavity, thereby explaining the structure-activity relationship that we observe.

Address correspondence to: Dr. C. G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: cnichols{at}cellbio.wustl.edu

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