TY - JOUR T1 - Molecular Basis of Inward Rectification: Structural Features of the Blocker Defined by Extended Polyamine Analogs JF - Molecular Pharmacology JO - Mol Pharmacol SP - 298 LP - 304 DO - 10.1124/mol.105.012377 VL - 68 IS - 2 AU - G. Loussouarn AU - L. J. Marton AU - C. G. Nichols Y1 - 2005/08/01 UR - http://molpharm.aspetjournals.org/content/68/2/298.abstract N2 - 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 KATP 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, V1/2 for spermine block = -10 ± 1 mV, Z = 2.9 ± 0.1, n = 19; V1/2 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. ER -