Talk:Structural Biochemistry/Membrane Proteins/Ion Channels

Cyclic-Nucleotide-Gated Ion Channels

Sensory signaling of cells is governed by unique cyclic nucleotide gated ion channels. One type of cyclic nucleotides gated ion (CNG) channels has to be activated “cooperatively” by several ligands. Another type of cyclic nucleotide gated ion channel can be “uncooperatively” regulated by a single ligand. Each type of CNG channel is unique and is found in different organisms. Mammals have adapted the cooperatively activated CNG channel, while research recently has found that bacteria and sea urchin sperm have adapted the non-cooperatively activated CNG ion channel. By comparing the newly discovered sea urchin sperm and bacteria to that of mammalian CNG ion gates, one can see the major differences in functions and structure.

Cooperative vs Uncooperative

Mammalian CNG ion gates also known as the classic ion gates are regulated cooperatively by several ligands. These ion gates have several binding sites for ligands. Successive binding of ligands onto CNG ion gate proteins can produce intense responses. For instance, the CNG channels can be closed by increasing the allosteric binding of ligands onto the gate proteins, or they can be rapidly opened by increased concentration of ligands. On the other hand, the newly researched CNG channel can be activated by a single ligand. The process that the newly researched CNG channel undergoes can be classified as uncooperative activation.

Structural difference

Classical CNG channels can be made up of four different A subunits and two different B subunits. Furthermore, the classical CNG exists as a heterotetramers which means that the gate can be made up of three different A subunits and one B subunits. The combination of subunits must equal four for it to be considered a classical CNG channel, but the subunits must be different. On the other hand, the new CNG channel forms tetramers which all the subunits are identical.

Both of the CNG polypeptides are made up of transmembrane domains S1-S6. The S4 domain is comprised of a voltage sensor for calcium, potassium, or sodium because of the charged Arg or Lys residues. Furthermore, the cyclic nucleotide binding domain in the C-terminal region is connected to S6 by a C-linker. The C-linker works to increase the contact of channel subunits which leads to tetramerization. In the new CNG channel, the C-linker region is made up of about 20 amino acids which does not promote subunit tetramerization. On the other hand, C-linker region of classical CNG channel is made up of about 80 amino acids that promote tetramerization. The increase in amino acid chain size shows the different ligand binding ability. The classical CNG channel with more amino acids allows for the tighter interaction of subunits which also means that they work cooperatively to open channels. While, the newly discovered CNG channel exhibits uncooperative ligand binding activation.

Ligand Binding Ligands bind differently to the two types of CNG channels. For instance, cAMP and cGMP both seen to bind to CNG channels interact in different manners. When cAMP binding to classical CNG channels, cAMP changes from a anti to syn conformation. On the other hand, cAMP binding to the new CNG channels, cAMP does not change conformations. The different CNG channels are able to change the conformations of cAMP which shows the selectivity of the different CNG channels. Furthermore, new CNG channels have a sensitivity range of 20-100 nM while classical CNG channels are in the range of 2-50µM. The reason for the difference in sensitivity is due to the absence of Arg residue in the CNBD binding region.