When people see the colorful world or smell a pleasant (or repulsive) scent, light or chemical signals are converted into electrical signals in their eyes and noses and signals which brain can recognize and process. Crucial for this signal conversion is a group of membrane proteins called cyclic nucleotide-gated (CNG) channels.

A team of scientists from the Kunming Institute of Zoology (KIZ) of Chinese Academy of Sciences (CAS), Columbia University and Tsinghua University recently determined the first high-resolution three-dimensional structure of a eukaryotic CNG channel. This structure provides unprecedented insights into CNG channel properties, how CNG channels open and close and how genetic mutations of CNG channels cause blindness. The study was published online in Nature. 

In vertebrates, vision and olfaction signal transduction relies on CNG channels. In photoreceptors, light activation of the photopigments decreases intracellular cyclic guanosine monophosphate (cGMP) concentration and closes CNG channels, resulting in membrane hyperpolarization. In olfactory sensory neurons, odorant activation of olfactory receptors increases intracellular cyclic adenosine monophosphate (cAMP) concentration and opens CNG channels, leading to membrane depolarization. Mutations in CNG channel genes have been associated with debilitating visual disorders such as retinitis pigmentosa and achromatopsia. 

CNG channels are members of the voltage-gated ion channel (VGIC) superfamily. VGICs have two structural and functional modules, a voltage-sensor domain (VSD) or voltage-sensor-like domain (VSLD) that moves in response to membrane voltage changes and a pore domain that opens and closes in response to VSD or VSLD movements. Although CNG channels possess a VSLD, they are not controlled by membrane voltage. This voltage-insensitivity is critical for proper phototransduction and olfactory transduction. Instead, CNG channels are controlled by intracellular cAMP or cGMP, which binds to the cytoplasmic C-terminus.  

Researchers used a cutting-edge technique called single particle electron cryo-microscopy (cryo‑EM) to obtain a 3.5 Å‑resolution cGMP-bound open-state structure of a full-length CNG channel from the nematode Caenorhabditis elegans. The structure reveals several novel and/or functionally important features, including a non-domain swapped configuration of its VSLD and pore domain, direct interactions between the C-terminus and both the pore domain and VSLD, and a segmented and restrained S4 transmembrane segment that evidently explains why CNG channels are not controlled by membrane voltage.

These and other structural features are in good agreement with CNG channel properties elucidated in extensive previous functional studies and provide new insights into the allosteric mechanisms of how cyclic nucleotide binding opens the channel. The structure also provides a blueprint for understanding and investigating the functional effects of hereditary disease-causing mutations.