POTASSIUM CHANNEL INACTIVATION PEPTIDE BLOCKS CYCLIC NUCLEOTIDE-GATEDCHANNELS BY BINDING TO THE CONSERVED PORE DOMAIN

Cyclic nucleotide-gated (CNG) channels in photoreceptors and olfactory neurons are activated by intracellular ligands (cAMP and cGMP) rather than voltage. Surprisingly, these channels share amino acid sequence homology with voltage-gated channels. Here we show that the distinct g ating mechanisms exhibited by CNG and voltage-gated channels share fea tures that reflect this structural homology. Thus, a 20 amino acid pep tide (''ball peptide'') derived from the Shaker-type K+ channel and re sponsible for its rapid inactivation also blocks CNG channels. Moreove r, the peptide selectively blocks open CNG channels and prevents chann el closure, showing that CNC channel activation, like activation of vo ltage-dependent K+ channels, involves the opening of a gate located on the intracellular side of the peptide-binding site. Amino acid substi tutions in the peptide cause similar changes in blocking affinity of C NG and K+ channels, suggesting a conserved binding site. Using a chime ric retinal/olfactory channel, we show that the difference in the pept ide affinity of the two CNG channels is due to a difference in the ami no acid sequence of the conserved pore-forming region, demonstrating t hat this domain forms part of the peptide receptor.