TY - JOUR
T1 - Molecular basis of inward rectification
T2 - Structural features of the blocker defined by extended polyamine analogs
AU - Loussouarn, G.
AU - Marton, L. J.
AU - Nichols, C. G.
PY - 2005/8
Y1 - 2005/8
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; V 1/2 for polyamine analogs varies from -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.
AB - 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; V 1/2 for polyamine analogs varies from -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.
UR - http://www.scopus.com/inward/record.url?scp=23044458353&partnerID=8YFLogxK
U2 - 10.1124/mol.105.012377
DO - 10.1124/mol.105.012377
M3 - Article
C2 - 15872118
AN - SCOPUS:23044458353
SN - 0026-895X
VL - 68
SP - 298
EP - 304
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 2
ER -