A disrupter of actin microfilaments impairs sulfonylurea-inhibitory gating of cardiac KATP channels.
The efficacy with which sulfonylurea drugs inhibit cardiac ATP-sensitive K+ (KATP) channels is reduced during metabolic compromise and cellular contracture. Disruption of the actin microfilament network, which occurs under similar conditions, reduces the sensitivity of the channel toward intracellular ATP. To investigate whether a disrupter of actin microfilaments could also affect the responsiveness of the KATP channel to sulfonylurea drugs, single-channel currents were measured in the inside-out configuration of excised patches from guinea pig ventricular myocytes. Treatment of the internal side of patches with deoxyribonuclease (DNase) I (100 micrograms/ml), which forms complexes with G actin and prevents actin filament formation, antagonized sulfonylurea-induced inhibition of KATP channels that was coupled with a loss of sensitivity to ATP. The apparent dissociation constant and Hill coefficient for the inhibitory effect of glyburide, a prototype sulfonylurea, on KATP-channel opening were, respectively, 0.13 microM and 0.95 before and 2.7 microM and 0.98 after DNase treatment. DNase did not alter intraburst kinetic properties of the channel. When DNase was denatured or coincubated with purified actin (200 micrograms/ml), it no longer decreased glyburide-induced channel inhibition. This suggests that sulfonylurea-inhibitory gating of cardiac KATP channels may also be regulated through a mechanism involving subsarcolemmal actin microfilament networks.
Brady
P A
PA
Department of Medicine and Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA.
Alekseev
A E
AE
Aleksandrova
L A
LA
Gomez
L A
LA
Terzic
A
A
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000199:Actins / Q000187:drug effects* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D003850:Deoxyribonuclease I / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D006358:Hot Temperature; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D000199:Actins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D003850:Deoxyribonuclease I; D005905:Glyburide