State-dependent block of CNG channels by dequalinium.
Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels with a high permeability for Ca(2+). Not surprisingly, they are blocked by a number of Ca(2+) channel blockers including tetracaine, pimozide, and diltiazem. We studied the effects of dequalinium, an extracellular blocker of the small conductance Ca(2+)-activated K(+) channel. We previously noted that dequalinium is a high-affinity blocker of CNGA1 channels from the intracellular side, with little or no state dependence at 0 mV. Here we examined block by dequalinium at a broad range of voltages in both CNGA1 and CNGA2 channels. We found that dequalinium block was mildly state dependent for both channels, with the affinity for closed channels 3-5 times higher than that for open channels. Mutations in the S4-S5 linker did not alter the affinity of open channels for dequalinium, but increased the affinity of closed channels by 10-20-fold. The state-specific effect of these mutations raises the question of whether/how the S4-S5 linker alters the binding of a blocker within the ion permeation pathway.
Rosenbaum
Tamara
T
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
Gordon-Shaag
Ariela
A
Islas
León D
LD
Cooper
Jeremy
J
Munari
Mika
M
Gordon
Sharona E
SE
D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D054815:Cyclic Nucleotide-Gated Cation Channels; D003868:Dequalinium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D014982:Xenopus laevis
D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D003868:Dequalinium