Enhancement of Voltage Sensitivity of a cGMP-gated Channel

Abstract

Activity of cyclic nucleotide-gated (CNG) cation channels underlies signal transduction in vertebrate visual receptors. These channels must be primarily activated by the binding of cGMP so that the activity of these highly specialized receptor channels be controlled by ligands in a finely graded manner required for transducing sensory stimuli of varying intensity. Significant voltage sensitivity of the channels would generate voltage-driven positive feedback and thus reduce the signal-transduction sensitivity. Indeed, the CNGA1 channel is only modestly voltage sensitive in low cGMP concentrations, and the voltage sensitivity vanishes with increasing cGMP concentration. We have found that loosening the attachment of the selectivity filter to the surrounding “pore shell” dramatically increases the channel's voltage sensitivity, which is independent of the positively charged residues in S4. Thus, proper attachment of the selectivity filter is essential to avoid significant, adverse voltage sensitivity in these channels.