title: Molecular basis of inward rectification: structural features of the blocker defined by extended polyamine analogs.
abstract: 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 microM, 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: G
authors.initials: G
authors.lastname: Loussouarn
authors.forename: L J
authors.initials: LJ
authors.lastname: Marton
authors.forename: C G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry*
chemical_list: D011073:Polyamines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying